CoChat
Sign Up
Cited by 146T-cell and B-cell ImmunologyImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

Tumor-specific IL-9–producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers

Open access
Lu, Yong, Hong, Bangxing, Li, Haiyan, Zheng, Yuhuan, Zhang, Mingjun, Wang, Siqing, Qian, Jianfei, Yi, Qing·2014·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1317431111PMC PMC3926063
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1073/pnas.1317431111

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 24 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Tc9 cells exhibit minimal specific cytolytic activity in vitro compared with Tc1 cells.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    Tc9 cells also produce IL-4, IL-10, and IL-17 after in vitro restimulation.

    “these Tc9 cells also produced some IL-4, IL-10, and IL-17 after in vitro restimulation (Fig. 2A and SI Appendix, Fig. S2A).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Tc9 cells express higher levels of IL-7Rα than Tc1 cells after transfer.

    “compared with Tc1 counterparts, the tumor-specific Tc9 cells expressed significantly higher levels of IL-7Rα, a prosurvival cytokine receptor”
    Quote in the paperSubstantial claim
  • Findingown data

    After adoptive transfer, Tc9 cells convert to IFN-γ-producing Tc1-like cells, especially at day 14.

    “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).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Tc1 cells continue to produce similar amounts of IFN-γ without other cytokines examined after transfer.

    “Compared with cells before transfer, Tc1 cells continued to produce similar amounts of IFN-γ without other cytokines examined.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 24
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Tc1 cells maintain IFN-γ and TNF-α production in spleens but production decreases in tumor tissues; Tc9 cells gain ability to produce IFN-γ and TNF-α in vivo and tumor-infiltrating Tc9 maintain production.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Tc9 cells have suppressed expression of Eomes and Tbx21 and up-regulated expression of Irf4 and Pu.1.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Tc9 cells produce significant amounts of IL-9 and IL-2 in vivo, indicating a less differentiated phenotype.

    “only Tc9 cells produced significant amounts of IL-9 and IL-2, which indicated a less differentiated phenotype of Tc9 cells (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data

    Tumor-infiltrating Tc1 and Tc9 cells are similar in their ability to lyse target tumor cells, although splenic Tc1 cells have slightly higher cytotoxicity than Tc9 cells.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Autoimmune vitiligo develops 4 weeks after transfer of Tc9 cells but not in Tc1 cell-treated mice.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IL-9 neutralization does not impair persistence of Tc9 cells or their ability to produce IFN-γ and GrzB.

    “IL-9 neutralization did not impair the persistence of Tc9 cells or their ability to produce IFN-γ and GrzB (SI Appendix, Fig. S5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tc9 cells keep IL-10 production in vivo, whereas IL-4 and IL-17 secretion is reduced over time.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the Pmel-1/B16 melanoma model, Tc9-cell transfer mediates sustained antitumor responses, whereas Tc1 cells only induce temporary tumor regression followed by relapse.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tumor rejection in the MC38-gp100 model is abrogated by anti-IL-9 treatment but not by IFN-γ neutralization.

    “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).”
    Quote in the paperSubstantial claim
    • 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.

  • May combine two claims.

    Findingown data

    Anti-IFN-γ treatment only ablates IFN-γ production from transferred Tc9 cells without affecting homing of cytolytic Tc9 cells to tumor tissues.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tc9 cells have diminished mRNA expression of Ifng and enhanced expression of Il9 and Il2 compared with Tc1 cells.

    “IL-9-skewed CD8 + T cells demonstrated diminished mRNA expression of Ifng but enhanced expression of Il9 and Il2”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adoptive transfer of OT-I Tc9 cells into mice bearing large established B16-OVA melanoma mediates significant tumor regression, complete cure, and long-term survival, whereas Tc1 cells only induce initial tumor shrinkage followed by relapse.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tc9 cells produce large amounts of IL-9 and minimal IFN-γ upon restimulation, whereas Tc1 cells produce large IFN-γ and undetectable IL-9.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Tc9-derived cells produce GrzB after transfer, and more GrzB-positive Tc9-derived cells are present than in Tc1-cell transferred mice.

    “We enumerated significantly more GrzB-positive Tc9derived cells than those in Tc1-cell transferred mice (Fig. 4 E and F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tc9 cell-transferred mice develop more than twofold Tc1-like cells compared with Tc1 cell-transferred mice 7 days after transfer, and the ratio increases over time.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Tc9 cells have enhanced persistence potential and capacity to acquire/maintain effector function after transfer.

    “Tc9 cells have substantially enhanced persistence potential and possess the capacity to acquire/maintain effector function after transfer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Th9 cell-derived IL-9 inhibits tumor progression and promotes greater tumor clearance than Th1 cells.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [17]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Host CTL responses may have contributed but were not required for antitumor efficacy of Tc9 cells in vivo.

    “host CTL responses may have contributed, but were not required, for the antitumor efficacy of Tc9 cells in vivo (SI Appendix, Fig. S7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Tc9 cells have a survival advantage or resistance to apoptosis rather than increased proliferation compared with Tc1 cells after transfer.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Tc9 cells may kill tumor cells independent of secreted IFN-γ, possibly using cytolytic enzymes, and IL-9 provides critical help to their migration into tumor sites to exert effector function.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [17]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • 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.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tc1 cells have a stronger therapeutic effect than Tc2 and regulatory CD8+ T cells.

    “Tc1 has stronger therapeutic effect than Tc2 and regulatory CD8 + T cells (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tc1 cells are superior to Tc17 cells in mediating tumor regression after transfer.

    “two more recent studies demonstrating that Tc1 cells are superior to Tc17 cells in mediating tumor regression after transfer (11,12).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Representative results from one of two performed experiments are shown.

    “Representative results from one of two performed experiments are shown.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Cytokine priming signals direct CD8+ T cells to acquire unique profiles that affect their ability to mediate specific immune responses.

    “Cytokine priming signals direct CD8 + T cells to acquire unique profiles that affect their ability to mediate specific immune responses (7,8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    PD-1 is a key T-cell exhaustion/inhibition pathway.

    “PD-1, a key T-cell exhaustion/inhibition pathway (35)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    IL-17 and IL-17-producing T cells are tumor-promoting factors and can mediate IL-6-induced Stat3 activation to generate a protumorigenic environment.

    “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)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    ACT has met with only modest success in humans, possibly because IL-2-induced T-bet high Tc1 cells display end-effector features and short lifespan.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    CD8+ T cells can acquire cytokine secreting phenotypes that require transcription factors similar to those of T helper cells.

    “CD8 + T cells can acquire cytokine secreting phenotypes that require transcription factors similar to those of T helper (Th) cells (9).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Tc1 cells secrete IFN-γ and kill tumor targets by releasing cytotoxic molecules such as GrzB and Perforin.

    “Tc1 cells secrete IFN-γ and kill tumor targets by releasing cytotoxic molecules such as GrzB and Perforin (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    Complete responses remain infrequent with most patients.

    “However, complete responses remain infrequent with most patients, and improvements to this approach are needed (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The animal study was approved by the Institutional Animal Care and Use Committee of Cleveland Clinic Foundation.

    “animal study was approved by the Institutional Animal Care and Use Committee of Cleveland Clinic Foundation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tumor-derived factors provide signals/conditions for effector T cells to become functionally exhausted in the tumor microenvironment.

    “tumor-derived factors could provide the necessary signals/conditions for effector T cells to become functionally exhausted in tumor microenvironment (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IFN-γ is a key factor linked to tumor rejection and is crucial for cytolytic function of CD8+ T cells.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Administration of naive or early effector T cells with active immunization and IL-2 can result in eradication of large established tumors.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-2 can augment antigen-driven acquisition of CD8+ effector T-cell phenotype with cytolytic function.

    “IL-2 can augment antigen-drive acquisition of CD8 + effector T-cell phenotype with cytolytic function”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

35 of 35

  • 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”
3 of 3

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Lu, Y., Hong, B., Li, H., Zheng, Y., Zhang, M., Wang, S., Qian, J., & Yi, Q.
Affiliations
  • Cleveland Clinic (US)
  • Jilin University (CN)
ORCID
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
DOI
10.1073/pnas.1317431111
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
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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review