The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index; none of the 24 sources its claims cite is checked for support yet.
Tumor-specific IL-9–producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers
Open accessAbstract
Significance: Our laboratory has identified a critical role of IL-9 in promoting endogenous tumor-specific cytotoxic T lymphocyte response. In this study, we found that differentiation of CD8 + T cells under T helper 9-polarizing conditions induces the development of an IL-9–producing less cytolytic IL-9–skewed CD8 + T (Tc9) cell subset. Noticeably, adoptive transfer of tumor-reactive Tc9 cells elicited greater antitumor responses against large established tumors than classic type-I CD8 + cytotoxic T cells that are used in clinical protocols. Importantly, Tc9 cells have substantially enhanced persistence potential and possess the capacity to acquire/maintain effector function after transfer. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. The ability of Tc9 cells to confer sustained antitumor responses might open an avenue for the advances of cancer immunotherapy.
Overview
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TL;DR
IL-9-skewed CD8+ Tc9 cells generated under Th9-polarizing conditions are less cytolytic in vitro than Tc1 cells but mediate superior antitumor responses against large established mouse tumors after adoptive transfer. Their efficacy depends critically on IL-9 production in vivo and is associated with greater persistence and conversion into IFN-γ- and granzyme-B-producing Tc1-like effector cells.
Key findings
- Tc9 cells showed diminished expression of Ifng, GrzB, Perforin, Eomes, and Tbx21, enhanced expression of Il9, Il2, Irf4, and Pu.1, and minimal specific cytolytic activity compared with OT-I Tc1 cells.
- In OT-I/B16-OVA melanoma, only Tc9 cells mediated significant regression of 10-day established tumors, resulting in complete cure and long-term survival; Tc1-treated mice relapsed 4 wk after infusion despite initial tumor shrinkage within the first 3 wk.
- Tc9 cells persisted better than Tc1 cells, had lower Annexin V+ apoptosis 4 d after transfer, were KLRG-1 low and IL-7Rα high, and developed more than twofold Tc1-like cells by day 7 and 25–30-fold by 3 wk compared with Tc1-transferred mice.
- In Pmel-1/B16 melanoma with cyclophosphamide, Tc9 cells mediated sustained antitumor responses while Tc1 cells induced only temporary regression followed by relapse; Tc9 transfer also produced autoimmune vitiligo 4 wk after transfer, not seen in Tc1-treated mice. IL-9 neutralization abrogated tumor rejection, whereas IFN-γ neutralization did not reach statistical significance.
Methods
- Naïve CD8+ T cells were primed under Th9-polarizing conditions to generate Tc9 cells and compared with IL-2-primed Tc1 cells.
- Adoptive transfer experiments used OT-I/B16-OVA, Pmel-1/B16, and MC38-gp100 mouse tumor models, with some mice receiving cyclophosphamide (250 mg/kg), dendritic cell vaccination, and four daily doses of rhIL-2.
- Main analyses included quantitative real-time PCR, ELISA, flow cytometry, CFSE dilution, Annexin V staining, in vitro cytotoxicity assays, and neutralizing antibodies against IL-9 or IFN-γ.
Limitations
- The paper does not state explicit limitations.
- Evident from the text: all therapeutic efficacy data are from mouse tumor models, with no human clinical testing reported.
- Evident from the text: Tc9 cells are less cytolytic in vitro and their cytokine profile is unstable after transfer, with IL-9 production decreasing and cells converting to IFN-γ-producing Tc1-like cells; the precise mechanism by which IL-9 promotes tumor infiltration is not fully resolved in this study.
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28 Own result · 19 Sources not found · 8 Own interpretation · 2 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“OT-I Tc1 cells showed strong cytotoxicity against tumor target cells, whereas OT-I Tc9 cells exhibited minimal specific cytolytic activity (Fig. 1C and SI Appendix, Fig. S1).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > IL-9-Producing Tc9 Cells Are Skewed Away from IFN-γ Production and
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“these Tc9 cells also produced some IL-4, IL-10, and IL-17 after in vitro restimulation (Fig. 2A and SI Appendix, Fig. S2A).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Characterization of Tc9 Cytokine Expression Profiles.
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“compared with Tc1 counterparts, the tumor-specific Tc9 cells expressed significantly higher levels of IL-7Rα, a prosurvival cytokine receptor”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Melanoma.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-9 production from Tc9 cells was decreased over time after transfer, and these cells were converted to IFN-γ-producing Tc1like cells especially at day 14 after transfer (Fig. 2B).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Characterization of Tc9 Cytokine Expression Profiles.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Compared with cells before transfer, Tc1 cells continued to produce similar amounts of IFN-γ without other cytokines examined.”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Characterization of Tc9 Cytokine Expression Profiles.
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tc9 cells had significantly down-regulated expression of the exhaustion markers, such as KLRG-1, PD-1, LAG3, and 2B4 (Fig. 4B)”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Melanoma.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This impaired Thy1.1 + CD8 + T-cell infiltration could also be demonstrated by the sharply decreased numbers of IFN-γ-producing and GrzB-producing Thy1.1 + CD8 + cells recovered from tumor sites (Fig. 6 B and C).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Therapeutic Effect of Tc9 Cells Critically Depends on IL-9.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in IL-9-neutralized mice, the number of tumor-infiltrating Thy1.1 + CD8 + T cells were substantially reduced compared with those in mice receiving isotype control or anti-IFN-γ antibodies.”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Therapeutic Effect of Tc9 Cells Critically Depends on IL-9.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The therapeutic effect of Tc9 cells depends specifically on IL-9 produced by the transferred Tc9 cells, rather than host-derived IL-9.
In the paper
“possibly, in part, owing to the extremely low surface expression of PD-1, a key T-cell exhaustion/inhibition pathway (35)”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Discussion
What the sources say
- Not matchedcites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 24
- The quote only partly states this claim. 2
- Probably not a substantial claim. 14
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ELISA results indicated that Tc1 cells maintained IFN-γ and TNF-α production in the spleens, but the production of these cytokines was significantly decreased in tumor tissues (Fig. 5F).”
- Also stated in: § Cyclophosphamide Synergizes with Pmel-1-Derived Tc9 Cells To · plain
“In contrast, Tc9 cells gained the ability to produce IFN-γ and TNF-α in vivo, and tumor-infiltrating Tc9 cells maintained the production of these cytokines compared with Tc9 cells in the spleens.”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Cyclophosphamide Synergizes with Pmel-1-Derived Tc9 Cells To
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
- Also stated in: § Cyclophosphamide Synergizes with Pmel-1-Derived Tc9 Cells To · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The expression of Eomes and Tbx21, the transcriptional master regulators that confer cytolytic lymphocyte lineage characteristics (18), were substantially suppressed in IL-9-skewed CD8 + T cells (Fig. 1B).”
- Also stated in: § IL-9-Producing Tc9 Cells Are Skewed Away from IFN-γ Production and · plain
“the expression of Irf4 and Pu.1, two transcription factors governing Th9-cell lineage development (19), was significantly up-regulated in Tc9 cells (Fig. 1B).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > IL-9-Producing Tc9 Cells Are Skewed Away from IFN-γ Production and
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § IL-9-Producing Tc9 Cells Are Skewed Away from IFN-γ Production and · plain
In the paper
“only Tc9 cells produced significant amounts of IL-9 and IL-2, which indicated a less differentiated phenotype of Tc9 cells (25).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Cyclophosphamide Synergizes with Pmel-1-Derived Tc9 Cells To
What the sources say
- Not matchedcites [25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“tumor-infiltrating Tc1 and Tc9 cells were similar in their ability to lyse target tumor cells, although splenic Tc1 cells had slightly higher cytotoxicity than Tc9 cells (Fig. 5G).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Cyclophosphamide Synergizes with Pmel-1-Derived Tc9 Cells To
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the development of autoimmune vitiligo was apparent 4 wk after transfer of Tc9 cells but was not observed in any of Tc1 celltreated mice (Fig. 5B).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Cyclophosphamide Synergizes with Pmel-1-Derived Tc9 Cells To
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-9 neutralization did not impair the persistence of Tc9 cells or their ability to produce IFN-γ and GrzB (SI Appendix, Fig. S5).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Therapeutic Effect of Tc9 Cells Critically Depends on IL-9.
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tc9 cells kept IL-10 production in vivo, whereas IL-4 and IL-17 secretion was reduced over time (Fig. 2B and SI Appendix, Fig. S2B).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Characterization of Tc9 Cytokine Expression Profiles.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tc9-cell transfer mediated sustained antitumor responses throughout the experiment, whereas Tc1 cells only induced temporary tumor regression, which was followed by relapse of aggressive tumor growth (Fig. 5A).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Cyclophosphamide Synergizes with Pmel-1-Derived Tc9 Cells To
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“tumor rejection was abrogated only by anti-IL-9 treatment, whereas neutralizing IFN-γ did not reach statistical significance compared with isotype control (Fig. 6A).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Therapeutic Effect of Tc9 Cells Critically Depends on IL-9.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The therapeutic effect of Tc9 cells depends specifically on IL-9 produced by the transferred Tc9 cells, rather than host-derived IL-9.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“anti-IFN-γ treatment only ablated the production of IFN-γ from transferred Tc9 cells, whereas the homing of cytolytic Tc9 cells to tumor tissues was not affected (Fig. 6 B and C).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Therapeutic Effect of Tc9 Cells Critically Depends on IL-9.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-9-skewed CD8 + T cells demonstrated diminished mRNA expression of Ifng but enhanced expression of Il9 and Il2”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > IL-9-Producing Tc9 Cells Are Skewed Away from IFN-γ Production and
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“only Tc9 cells mediated a significant tumor regression resulting in a complete cure and long-term survival, whereas Tc1 cell-treated mice relapsed 4 wk after T-cell infusion despite the initial tumor shrinkage within the first 3 wk (Fig. 3A).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Melanoma.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“OT-I Tc1 cells produced a large amount of IFN-γ, whereas Tc9 cells released a minimal amount of IFN-γ but secreted a large amount of IL-9 (Fig. 2A).”
- Also stated in: § Characterization of Tc9 Cytokine Expression Profiles. · plain
“production of IL-9, IL-4, IL-10, or IL-17 from Tc1 cells was undetectable”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Characterization of Tc9 Cytokine Expression Profiles.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
- Also stated in: § Characterization of Tc9 Cytokine Expression Profiles. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We enumerated significantly more GrzB-positive Tc9derived cells than those in Tc1-cell transferred mice (Fig. 4 E and F).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Melanoma.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tc9 cell-transferred mice had already developed more than twofold Tc1-like cells compared with those in Tc1 cell-transferred mice 7 d after the transfer and this ratio kept increasing over time (Fig. 4D).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Melanoma.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tc9 cells have substantially enhanced persistence potential and possess the capacity to acquire/maintain effector function after transfer.”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Significance
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“we and others reported that Th9 cell-derived IL-9 not only inhibited tumor progression, but also promoted greater tumor clearance than Th1 cells that have traditionally been considered as the most efficient CD4 + T-cell subset to generate antitumor immunity (15)(16)(17).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“host CTL responses may have contributed, but were not required, for the antitumor efficacy of Tc9 cells in vivo (SI Appendix, Fig. S7).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Therapeutic Effect of Tc9 Cells Critically Depends on IL-9.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggested that the persistence of Tc9 cells, which might be one of the key reasons for the rejection of established tumor after transfer, may be the result of a survival advantage or resistance to apoptosis rather than increased proliferation of the cells.”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Melanoma.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“these results thus far suggested that Tc9 cells may kill tumor cells independent of their secreted IFN-γ, possibly by using the cytolytic enzymes, and IL-9 provided critical help to their migration into tumor sites to exert effector function”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Therapeutic Effect of Tc9 Cells Critically Depends on IL-9.
What the sources say
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The therapeutic effect of Tc9 cells depends specifically on IL-9 produced by the transferred Tc9 cells, rather than host-derived IL-9.
- Not matched
In the paper
“Tc1 has stronger therapeutic effect than Tc2 and regulatory CD8 + T cells (10).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“two more recent studies demonstrating that Tc1 cells are superior to Tc17 cells in mediating tumor regression after transfer (11,12).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Representative results from one of two performed experiments are shown.”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Materials and Methods
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Cytokine priming signals direct CD8 + T cells to acquire unique profiles that affect their ability to mediate specific immune responses (7,8).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
In the paper
“PD-1, a key T-cell exhaustion/inhibition pathway (35)”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Discussion
What the sources say
- Not matchedcites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
In the paper
“IL-17 and IL-17-producing T cells are tumor-promoting factors and can mediate IL-6-induced Stat3 activation to generate protumorigenic environment (13)”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Not matched
In the paper
“ACT has met with only modest success in humans, possibly due to the fact that IL-2-induced T-bet high Tc1 cells display end-effector features and short lifespan (21).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Discussion
What the sources say
- Not matchedcites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“CD8 + T cells can acquire cytokine secreting phenotypes that require transcription factors similar to those of T helper (Th) cells (9).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
In the paper
“Tc1 cells secrete IFN-γ and kill tumor targets by releasing cytotoxic molecules such as GrzB and Perforin (9).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
In the paper
“However, complete responses remain infrequent with most patients, and improvements to this approach are needed (2).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“animal study was approved by the Institutional Animal Care and Use Committee of Cleveland Clinic Foundation.”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Materials and Methods
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“tumor-derived factors could provide the necessary signals/conditions for effector T cells to become functionally exhausted in tumor microenvironment (33).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Discussion
What the sources say
- Not matchedcites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“IFN-γ, which is well established as a key factor linked to tumor rejection and is crucial for cytolytic function of CD8 + T cells (32).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Discussion
What the sources say
- Not matchedcites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
In the paper
“administration of naïve or early effector T cells in combination with active immunization and IL-2 can result in eradication of large established tumors (4).”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity
What the sources say
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“IL-2 can augment antigen-drive acquisition of CD8 + effector T-cell phenotype with cytolytic function”
§ Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers > Discussion
What the sources say
- Not matchedcites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The paper relies on this without support.
The mouse tumor models used are predictive of human adoptive cell therapy for cancers.
“These findings have clinical implications for the improvement of CD8 + T-cell-based adoptive immunotherapy of cancers.”
“The ability of tumor-reactive Tc9 cells to confer sustained antitumor responses against large established tumors might open an avenue to overcome the challenges encountered by current ACT protocols.”
The paper relies on this without support.
The conversion of Tc9 cells to IFN-γ-producing Tc1-like cells after transfer reflects lineage plasticity rather than selective outgrowth of a pre-existing Tc1-like subpopulation.
“the sufficient lineage plasticity of Tc9 cells allows these cells subsequently to differentiate into long-lasting IFN-γ-producing Tc1like effector cells upon transfer.”
The paper relies on this without support.
The therapeutic effect of Tc9 cells depends specifically on IL-9 produced by the transferred Tc9 cells, rather than host-derived IL-9.
“Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo.”
“tumor rejection was abrogated only by anti-IL-9 treatment”
Citations
Cites
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
Rosenberg, S. A., Yang, J. C., Sherry, R. M., Kammula, U. S., Hughes, M. S., Phan, G. Q., Citrin, D. E., Restifo, N. P., Robbins, P. F., Wunderlich, J. R., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0116 · Cited by 2,208
Joshi, N. S., Cui, W., Chandele, A., Lee, H. K., Urso, D. R., Hagman, J., Gapin, L., & Kaech, S. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.010 · Cited by 1,861
Adoptive immunotherapy for cancer: harnessing the T cell response
Restifo, N. P., Dudley, M. E., & Rosenberg, S. A. (2012) · Nature Reviews Immunology · doi:10.1038/nri3191 · Cited by 1,688
Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin
Intlekofer, A. M., Takemoto, N., Wherry, E. J., Longworth, S. A., Northrup, J. T., Palanivel, V., Mullen, A. C., Gasink, C. R., Kaech, S. M., Miller, J. D., et al. (2005) · Nature Immunology · doi:10.1038/ni1268 · Cited by 1,293
The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design
Waldmann, T. A. (2006) · Nature reviews. Immunology · doi:10.1038/nri1901 · Cited by 1,174
Gattinoni, L., Finkelstein, S. E., Klebanoff, C. A., Antony, P. A., Palmer, D. C., Spiess, P. J., Hwang, L. N., Yu, Z., Wrzesinski, C., Heimann, D. M., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050732 · Cited by 1,073
Gattinoni, L. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24480 · Cited by 947
Overwijk, W. W., Theoret, M. R., Finkelstein, S. E., Surman, D. R., de Jong, L. A., Vyth‐Dreese, F. A., Dellemijn, T. A. M., Antony, P. A., Spiess, P. J., Palmer, D. C., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030590 · Cited by 926
IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway
Wang, L., Yi, T., Kortylewski, M., Pardoll, D. M., Zeng, D., & Yu, H. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090207 · Cited by 868
Cited by
Sorted by citations
Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment
Ma, X., Bi, E., Lu, Y., Su, P., Huang, C., Liu, L., Wang, Q., Yang, M., Kalady, M. F., Qian, J., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.04.002 · Cited by 1,033
Self-citationZander, R., Schauder, D., Xin, G., Nguyen, C. P., Wu, X., Zajac, A. J., & Cui, W. (2019) · Immunity · doi:10.1016/j.immuni.2019.10.009 · Cited by 660
“Previous reports have identified that adoptive cell therapy (ACT) with CD4+ T cells, can improve CD8+ T cell responses and enhance control over tumor progression (Lu et al. 2014; Muranski et al. 2008; Purwar et al. 2012; Vegran et al.”
BackgroundThe Roles of CD8+ T Cell Subsets in Antitumor Immunity
Paul, M. S., & Ohashi, P. S. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.06.003 · Cited by 635
The development and in vivo function of T helper 9 cells
Kaplan, M. H., Hufford, M. M., & Olson, M. R. (2015) · Nature Reviews Immunology · doi:10.1038/nri3824 · Cited by 384
Heterogeneity in the Differentiation and Function of CD8+ T Cells
Mittrücker, H.-W., Visekruna, A., & Huber, M. (2014) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-014-0293-y · Cited by 325
“In a mouse tumor model, transferred Tc9 cells acquired a Tc1 memory phenotype, indicating that memory formation was associated with the transition into Tc1 cells (Lu et al. 2014).”
Influential
Metadata
- Authors
- Lu, Y., Hong, B., Li, H., Zheng, Y., Zhang, M., Wang, S., Qian, J., & Yi, Q.
- Affiliations
- Cleveland Clinic (US)
- Jilin University (CN)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-01-27
- Volume
- 111
- Issue
- 6
- Pages
- 2265-2270
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3926063
- OpenAlex
- W2075253497
- Semantic Scholar
- b23e5e7210f5e3c87dfe955508ea4e51888215ee
- Cited by
- 146
- References
- 36
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 13 · 2023: 13 · 2022: 13 · 2021: 14 · 2020: 18 · 2019: 8 · 2018: 12 · 2017: 7 · 2016: 9 · 2015: 10 · 2014: 9
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- Multiple Myeloma Research Foundation
- Leukemia and Lymphoma Society
- Cleveland Clinic
- National Cancer Institute (P50 CA142509, R01CA138398, R01 CA138402, R01 CA138398, R01 CA163881, R01CA163881, CA142509, R01CA138402)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- IL-9, CD8+ T cells, Tc1 cells, adoptive T cell therapy, antitumor immunity, melanoma, cytotoxic T lymphocytes, granzyme B, interferon-gamma, IL-7 receptor alpha, KLRG1, T cell self-renewal, tumor-specific T cells
- MeSH terms
- Animals, Cell Differentiation, Cyclophosphamide, Enzyme-Linked Immunosorbent Assay, Interferon-gamma, Melanoma, Experimental, Cytokines, Immunotherapy, Adoptive, Interleukin-9, CD8-Positive T-Lymphocytes, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-23, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-23 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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