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Cited by 109Cancer Immunotherapy and BiomarkersRenal Transplantation Outcomes and TreatmentsTransplantation: Methods and Outcomes

Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation

Open access
Esfahani, Khashayar, Al-Aubodah, Tho-Alfakar, Thebault, Pamela, Lapointe, Réjean, Hudson, Marie, Johnson, Nathalie A., Baran, Dana, Bhulaiga, Najwa +4 more·2019·Nature Communications
DOI 10.1038/s41467-019-12628-1PMC PMC6797722
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Abstract

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (T reg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated T reg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.

AI snapshot

Written from the paper’s full text.

TL;DR

In a single patient with a long-standing HLA-identical kidney transplant and metastatic melanoma, PD-1 blockade caused allograft rejection and immune-related adverse events, but adding sirolimus after steroid control maintained anti-tumor benefit and prevented further rejection or irAEs. Immune profiling suggested sirolimus dampened cytotoxic T cell activation and eosinophilia while preserving IFN-γ responses and elevated Treg numbers.

Key findings

  • The patient was a 57-year-old female with a kidney transplant from 1985 and recurrent melanoma. On pembrolizumab, her axillary mass decreased from 13.8 × 6.4 cm to 7.5 × 3.6 cm at W7 (partial response by RECIST 1.1), but at W9 creatinine rose from 57 to 310 μmol/L (reference 55–110 μmol/L) with grade 2 rash and grade 2 colitis. After steroids, sirolimus 2.5 mg daily was added at W15 and pembrolizumab resumed at W16; at W22 she had stable disease with a 3.6 cm short-axis mass and no further irAEs or rejection.
  • During rejection, activated (HLA-DR+) and cycling (Ki-67+) CD4+ and CD8+ T cells increased greatly and returned to baseline under ICI-mTORi; the increased CD8+ proportion at rejection was reversed under combination therapy.
  • Rejection featured upregulated IL-5 and eotaxin, eosinophilia, elevated CRP, and modest increases in TNF-α, IL-6, IL-17A, and IP-10/CXCL10. Under ICI-mTORi, eosinophilia and all these mediators except IL-6 and eotaxin returned to baseline, while serum IFN-γ was significantly elevated.
  • IFN-γ+ CD8+ T cells, largely granzyme B+, were elevated during rejection; under ICI-mTORi the fraction of IFN-γ+ CD8+ T cells decreased but remained above baseline, and IFN-γ+ CD4+ T cell numbers increased. Treg (CD3+CD4+CD25HighCD127LowFoxp3+Helios+) numbers and proportions increased during rejection and remained elevated under ICI-mTORi.

Methods

  • Single-patient case report with peripheral blood collected at four time points: W2 pre-PD-1, W9 rejection onset, W10 peak rejection, and W22 on pembrolizumab plus sirolimus.
  • Multi-parametric flow cytometry assessed T cell subsets, activation/proliferation markers, intracellular cytokines, and Treg markers; plasma cytokines/chemokines were measured by multiplex assay; in vitro PBMC cultures used anti-CD3 with or without sirolimus versus DMSO, including a 25-year-old healthy male control.
  • Statistical analysis used GraphPad Prism 7; one-way ANOVA was performed for in vitro multiple comparisons with α = 0.05.

Limitations

  • Stated: no tumor and/or renal biopsy was obtained during irAEs because timely biopsy required reversal of therapeutic anticoagulation for the patient’s upper extremity thrombosis; it is possible the patient would not have had further extra-renal toxicities on PD-1 rechallenge alone; and the patient chose to continue treatment to maximize tumor response while accepting dialysis/rejection risk rather than watch-and-wait.
  • Evident: this is a single case report (n = 1) with no control group, limiting generalizability; several flow cytometric analyses were completed once, as noted in the figure legends, and no biopsy confirmed the immune crosstalk between toxicity sites and the tumor microenvironment.

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

Integrity signals

Registry

Crossref · 10.1038/s41467-019-12628-1

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 43 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Elevated Treg cell numbers in peripheral blood were maintained with sirolimus co-treatment.

    “while elevated Treg cell numbers in the peripheral blood were maintained”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.
  • Findingown data

    Serum IFN-γ levels increased with addition of sirolimus treatment.

    “serum IFN-γ levels increased with the addition of sirolimus treatment”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: IFN-γ production by T cells is a marker of anti-tumor immune surveillance and efficacy.
  • Findingown data

    Significant eosinophilia was noted during allograft rejection.

    “strong increase in the numbers of circulating eosinophils”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
  • Findingown data

    Circulating regulatory T (Treg) cell responses were noted during allograft rejection.

    “circulating regulatory T (Treg) cell responses were noted during allograft rejection”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.
  • Findingown data

    Co-treatment with sirolimus abated cytotoxic T cell numbers.

    “Co-treatment with sirolimus abated cytotoxic T cell numbers”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
  • May combine two claims. 31
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    In a melanoma patient with a kidney allograft, PD-1 blockade resulted in organ rejection and colitis.

    “In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The clinical episode of rising creatinine and irAEs represented renal allograft rejection despite the absence of a biopsy.

  • May combine two claims.

    Findingown data

    In that patient, addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance.

    “the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: IFN-γ production by T cells is a marker of anti-tumor immune surveillance and efficacy.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.

  • The quote only partly states this claim.

    Findingown data

    Elevated serum eotaxin levels were noted during allograft rejection.

    “upregulation of the eosinophil-recruiting chemokine, eotaxin”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    Proportions of circulating CD8+ T cells over CD4+ T cells increased at the time of rejection, and this trend was reversed under ICI-mTORi.

    “we noticed an increase in the proportions of circulating CD8+ T cells over CD4+ T cells at the time of rejection, a trend which was reversed under ICI-mTORi”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    All irAEs subsided and creatinine returned to normal by W11 after steroid treatment.

    “All irAEs subsided, and creatinine returned to normal by W11.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Stably suppressive Treg cell numbers and proportions remained elevated following ICI-mTORi.

    “and remained elevated following ICI-mTORi”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.

  • May combine two claims.

    Findingown data

    Treg cells at peak of rejection expressed only slightly higher levels of CD25, which returned to normal levels following ICI-mTORi co-treatment.

    “Treg cells at the peak of rejection expressed only slightly higher levels of CD25 which returned to normal levels following ICI-mTORi co-treatment”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.

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

    Findingown data

    TNF-α modestly increased during rejection.

    “Modest increases in other inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-17A were observed”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    Among CD8+ T cells, the fraction of IFN-γ-producing cells decreased under ICI-mTORi but remained higher than baseline levels.

    “Among CD8+ T cells, the fraction of IFN-γ-producing cells decreased under ICI-mTORi but remained higher than baseline levels”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    The patient had ongoing anti-tumor benefit, with stable disease per RECIST 1.1 at 6-month follow-up on W22.

    “had ongoing anti-tumor benefit, as demonstrated by a 3.6 cm short axis diameter of the axillary mass, representing stable disease per RECIST 1.1 (Supplementary Fig. 1A), at a 6-month follow-up scan on W22.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During rejection, FOXP3 expression increased substantially but was restored to baseline levels with mTORi and PD-1 blockade.

    “During the rejection phase, expression of FOXP3, the master lineage-defining transcription factor of Treg cells, increased substantially but was restored to baseline levels with mTORi and PD-1 blockade”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.

  • May combine two claims.

    Findingown data

    On W7, the patient's axillary mass decreased from 13.8 × 6.4 cm to 7.5 × 3.6 cm on CT, representing partial response per RECIST 1.1.

    “On W7, the patient’s axillary mass had decreased from total conglomerate dimensions of 13.8 × 6.4 cm to 7.5 × 3.6 cm on CT scans, thus representing a partial response according to RECIST 1.1 criteria”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On W9, the patient developed a grade 2 diffuse body maculopapular rash and a grade 2 colitis.

    “as well as other irAEs, consisting of a grade 2 diffuse body maculopapular rash and a grade 2 colitis”
    Quote in the paperNot a substantial claim

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

    Findingown data

    IL-17A modestly increased during rejection.

    “Modest increases in other inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-17A were observed”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    Addition of mTORi for irAE control resulted in increased numbers of CD4+ T cells producing IFN-γ, although their proportions remained unchanged.

    “the addition of mTORi for irAE control resulted in increased numbers of CD4+ T cells producing IFN-γ, although their proportions remained unchanged”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    During re-challenge with pembrolizumab in combination with sirolimus, global T cell activation and proliferation was abated, although IFN-γ-producing CD4+ T cells and cytotoxic CD8+ T cells persisted in circulation.

    “during a re-challenge with pembrolizumab in combination with sirolimus, global T cell activation and proliferation was abated, although IFN-γ-producing CD4+ T cells and cytotoxic CD8+ T cells persisted in circulation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    After prednisone taper and addition of sirolimus, the patient did not experience further irAEs or allograft rejection.

    “The patient did not experience any further irAEs or allograft rejection”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The clinical episode of rising creatinine and irAEs represented renal allograft rejection despite the absence of a biopsy.

  • May combine two claims.

    Findingown data

    IP-10/CXCL10 was significantly increased during renal allograft rejection and returned to baseline levels following re-challenge with anti-PD-1 under mTORi.

    “IP-10/CXCL10 was also significantly increased during renal allograft rejection and returned to baseline levels following re-challenge with anti-PD-1 under mTORi.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingcitation

    In this patient, IL-6, TNF-α and IL-17A were elevated during rejection phase and were likely promoting observed skin and gastrointestinal toxicities.

    “In this patient, several other inflammatory cytokines, mainly IL-6, TNF-α and IL-17A, were also elevated during the rejection phase, and were likely promoting the observed concomitant skin and gastrointestinal toxicities29–31.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Bernardo, D. et al. IL-6 promotes immune responses in human ulcerative colitis and induces a skin-homing phenotype in the dendritic cells and Tcells they stimulate. Eur. J. Immunol. 42, 1337–1353 (2012). source

      Not checked in the free run.

    • cites [30] Guilloteau, K. et al. Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α recapitulates some features of psoriasis. J. Immunol. 184, 5263–5270 (2010). source

      Not checked in the free run.

    • cites [31] Esfahani, K. & Miller, W. H. Jr. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N. Engl. J. Med 376, 1989–1991 (2017). source

      Not checked in the free run.

    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    Levels of most of these cytokines returned to baseline following high dose steroid administration and did not rise upon rechallenge.

    “The levels of most of these cytokines returned to baseline following high dose steroid administration and did not rise upon rechallenge with”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Findingown data

    In our case, the addition of sirolimus did not impair the numbers of IFN-γ secreting T cells and the high circulating levels of this cytokine.

    “In our case, the addition of sirolimus did not seem to impair the numbers of IFN-γ secreting T cells and the high circulating levels of this cytokine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Most cytokine levels returned to baseline following high dose steroid administration and did not rise upon rechallenge with ICI-mTORi.

    “The levels of most of these cytokines returned to baseline following high dose steroid administration and did not rise upon rechallenge with ICI-mTORi.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    mTOR is a central integrator of metabolic and immune signals associated with T cell activation and is a critical driver and modulator of T cell differentiation, function, and homeostasis.

    “the mammalian target of rapamycin (mTOR), a central integrator of the metabolic and immune signals associated with T cell activation, is emerging as a critical driver and modulator of T cell differentiation, function, and homeostasis6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Waickman, A. T. & Powell, J. D. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249, 43–58 (2012). source

      Not checked in the free run.

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

    Premisecitation

    The mTOR pathway plays a pivotal role in integrating signals at the cellular level and promotes autoimmunity and carcinogenesis.

    “The mTOR pathway has long been recognized to play a pivotal role in integrating signals at the cellular level and promote autoimmunity and carcinogenesis18,19.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Perl, A. mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann. N. Y Acad. Sci. 1346, 33–44 (2015). source

      Not checked in the free run.

    • cites [19] Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Anecdotal use of mTOR inhibition as primary prevention was reported for patients with kidney transplants.

    “For patients with kidney transplants, anecdotal use of mTOR inhibition (mTORi) as primary prevention was reported12,13.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Sadaat, M. & Jang, S. Complete tumor response to pembrolizumab and allograft preservation in renal allograft recipient on immunosuppressive therapy. J. Oncol. Pr. 14, 198–199 (2018). source

      Not checked in the free run.

    • cites [13] Barnett, R., Barta, V. S. & Jhaveri, K. D. Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab. N. Engl. J. Med 376, 191–192 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Although Treg cell proliferation and activation was dampened by ICI-mTORi co-therapy, Treg cell numbers remained elevated thereafter.

    “although Treg cell proliferation and activation was dampened by ICI-mTORi co-therapy, Treg cell numbers remained elevated thereafter”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.

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

    Premisecitation

    Eosinophil infiltration is a prominent marker of allograft rejection and predicts a poor prognosis.

    “eosinophil infiltration is a prominent marker of allograft rejection and predicts a poor prognosis25,26.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Weir, M. R. et al. The prognostic value of the eosinophil in acute renal allograft rejection. Transplantation 41, 709–712 (1986). source

      Not checked in the free run.

    • cites [26] Braun, M. Y. et al. IL-5 and eosinophils mediate the rejection of fully histoincompatible vascularized cardiac allografts: regulatory role of alloreactive CD8(+) T lymphocytes and IFN-gamma. Eur. J. Immunol. 30, 1290–1296 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    While T cells were efficiently activated in vitro, a large proportion failed to proliferate and partake in downstream immune response.

    “This indicates that while T cells were efficiently activated, a large proportion failed to proliferate and partake in any downstream immune response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Results suggest that while irAEs-related inflammation was abated systemically with corticosteroids and mTORi, increased IFN-γ may indicate continued and efficient tumor control.

    “Overall, these results suggest that while irAEs-related inflammation was abated systemically with the addition of corticosteroids and mTORi, the increased IFN-γ may indicate continued and efficient tumor control.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IFN-γ production by T cells is a marker of anti-tumor immune surveillance and efficacy.

  • May combine two claims.

    Interpretationown data

    ICI-mTORi combination therapy promoted a state of functional tolerance without a loss of immune-mediated anti-tumor activity.

    “Thus, ICI-mTORi combination therapy promoted a state of functional tolerance without a loss of immune-mediated anti-tumor activity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.
    • Rests on an assumption: IFN-γ production by T cells is a marker of anti-tumor immune surveillance and efficacy.
    • Rests on an assumption: Treg cells are critical for allograft tolerance and tissue homeostasis.

  • May combine two claims.

    Interpretationown data

    Results suggest that while addition of mTORi was crucial in controlling activation and expansion of cytotoxic CD8+ T cells, IFN-γ+ CD8+ T cells with potential anti-tumor functions were still found in greater numbers in peripheral blood compared to baseline.

    “Overall, these results suggest that while the addition of mTORi was crucial in controlling the activation and expansion of cytotoxic CD8+ T cells, as shown earlier, IFN-γ+ CD8+ T cells with potential anti-tumor functions were still found in greater numbers in peripheral blood when compared to baseline.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IFN-γ production by T cells is a marker of anti-tumor immune surveillance and efficacy.

  • May combine two claims.

    Interpretationown data

    Sirolimus hinders T cell activation and thereby prevents expansion and accumulation of CD8+ T cells.

    “indicating a role for sirolimus in hindering T cell activation and thereby preventing the expansion and accumulation of CD8+ T cells”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

  • May combine two claims.

    Premisecitation

    Although the mTOR pathway can be activated in the majority of melanomas, mTOR inhibitors have not been proven effective in this clinical setting.

    “Although the mTOR pathway can be activated in the majority of melanomas, mTOR inhibitors have not been proven effective in this clinical setting20–22.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] Populo, H., Lopes, J. M. & Soares, P. The mTOR signalling pathway in human cancer. Int J. Mol. Sci. 13, 1886–1918 (2012). source

      Not checked in the free run.

    • cites [21] Wu, X. et al. PI3K/AKT/mTOR pathway inhibitors inhibit the growth of melanoma cells with mTOR H2189Y mutations in vitro. Cancer Biol. Ther. 19, 584–589 (2018). source

      Not checked in the free run.

    • cites [22] Karbowniczek, M., Spittle, C. S., Morrison, T., Wu, H. & Henske, E. P. mTOR is activated in the majority of malignant melanomas. J. Invest Dermatol 128, 980–987 (2008). source

      Not checked in the free run.

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

    Premisecitation

    A compensatory delayed expansion of Treg cells in response to inflammation is known to control immune responses and maintain peripheral tolerance in various disease systems.

    “A similar compensatory delayed expansion of Treg cells in response to inflammation is known to control immune responses and maintain peripheral tolerance in various disease systems43.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Gupta, S. et al. Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs. J. Clin. Invest 122, 2395–2404 (2012). source

      Not checked in the free run.

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

    Premisecitation

    IFN-γ is critical for anti-PD-1 efficacy by promoting immune surveillance.

    “In regards to tumor control, IFN-γ has pleiotropic effects, and is critical for anti-PD-1 efficacy by promoting immune surveillance37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Karachaliou, N. et al. Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther. Adv. Med Oncol. 10, 1758834017749748 (2018). source

      Not checked in the free run.

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

    Premisecitation

    IL-10 is a potent immunomodulatory cytokine produced by protective immune cell subsets, including Treg cells, and known to play a key role in inducing and maintaining allograft tolerance.

    “In accordance with Treg cell expansion during allograft rejection, there was a substantial increase in serum IL-10—a potent immunomodulatory cytokine produced by protective immune cell subsets, including Treg cells, and known to play a key role in inducing and maintaining allograft tolerance45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Pearce, E. L. Metabolism in T cell activation and differentiation. Curr. Opin. Immunol. 22, 314–320 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    mTOR inhibition promotes the induction and maintenance of FOXP3 expression and consequential Treg cell development in humans.

    “Interestingly, mTOR inhibition has been described to promote the induction and maintenance of FOXP3 expression and consequential Treg cell development in humans41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Chapman, N. M. & Chi, H. mTOR signaling, Tregs and immune modulation. Immunotherapy 6, 1295–1311 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Selective use of mTORi in combination with PD-1 blockade may promote and/or maintain Treg cell functions amidst evolving anti-tumor immune responses and prevent graft rejection.

    “Thus, our results suggest that the selective use of mTORi in combination with PD-1 blockade may promote and/or maintain Treg cell functions amidst evolving anti-tumor immune responses and prevent graft rejection.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: mTOR is a central integrator of T cell activation signals, playing a critical role in driving T cell differentiation and function and controlling multiple metabolic programs.

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

    Study design and conductown data

    A tumor and/or renal biopsy during the immune-related adverse events could not be performed in a timely manner due to the therapeutic anticoagulation reversal required for the patient's upper extremity thrombosis.

    “A tumor and/or renal biopsy during the immune-related adverse events would have been helpful to assess immune crosstalk between the site of toxicity and the tumor microenvironment but could not be performed in timely manner due to the therapeutic anticoagulation reversal (for the patient’s upper extremity thrombosis) that was required.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Eosinophilia is a toxicity frequently associated with anti-PD-1 therapy.

    “Recent reports suggest that eosinophilia is a toxicity frequently associated with anti-PD-1 therapy27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Bernard-Tessier, A. et al. Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies. Eur. J. Cancer 81, 135–137 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Key recent reviews of all transplant cases treated with ICIs highlight the vast heterogeneity of immunosuppression regimens used and the void of translational data guiding treatment decisions.

    “Key recent reviews of all the transplant cases treated with ICIs highlight the vast heterogeneity of the immunosuppression regimens used in this setting the void of any translational data guiding treatment decisions7–9.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Aguirre, L. E., Guzman, M. E., Lopes, G. & Hurley, J. Immune checkpoint inhibitors and the risk of allograft rejection: a comprehensive analysis on an emerging issue. Oncologist 24, 394–401 (2019). source

      Not checked in the free run.

    • cites [8] Abdel-Wahab, N. et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J. Immunother. Cancer 7, 106 (2019). source

      Not checked in the free run.

    • cites [9] De Bruyn, P. et al. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go? Curr. Opin. Oncol. 31, 54–64 (2019). source

      Not checked in the free run.

41 of 41

  • The paper relies on this without support.

    Peripheral blood immune measurements reflect the immune processes occurring in the allograft and tumor.

    “we present a detailed immunophenotyping of peripheral blood from a patient who underwent kidney allograft rejection”

  • The paper relies on this without support.

    IFN-γ production by T cells is a marker of anti-tumor immune surveillance and efficacy.

    “serum levels of (IFN)-γ, an important anti-tumor cytokine”

  • The paper relies on this without support.

    Treg cells are critical for allograft tolerance and tissue homeostasis.

    “regulatory T (TREG) cells, an adaptive immune subset critical for allograft tolerance and tissue homeostasis”

  • The paper relies on this without support.

    The clinical episode of rising creatinine and irAEs represented renal allograft rejection despite the absence of a biopsy.

    “Although a biopsy was not performed in our patient”

  • The paper relies on this without support.

    IFN-γ is a pleiotropic cytokine that can exert opposite allograft outcomes depending on the immune landscape.

    “IFN-γ is a well-established pleiotropic cytokine with the power of exerting opposite allograft outcomes depending on the immune landscape.”

  • The paper relies on this without support.

    mTOR is a central integrator of T cell activation signals, playing a critical role in driving T cell differentiation and function and controlling multiple metabolic programs.

    “mTOR is a central integrator of these signals, playing a critical role in driving T cell differentiation and function and controlling multiple metabolic programs.”

  • The paper relies on this without support.

    Allograft rejection is associated with severe and potentially life-threatening complications.

    “Given the severe and potentially life-threating complications associated with allograft rejection, our data are timely in providing strong basic science, as well as clinical rationale for the ICI-mTORi combination as a potential standard of care for these patients.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cytokine measurements described as serum and plasma

    Minor

    The results describe IFN-γ levels as measured in serum, but the methods state that cytokine measurements used cryopreserved plasma. These are different specimen types.

1 of 1

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Authors
Esfahani, K., Al-Aubodah, T.-A., Thebault, P., Lapointe, R., Hudson, M., Johnson, N. A., Baran, D., Bhulaiga, N., Takano, T., Cailhier, J.-F., Piccirillo, C. A., & Miller, W. H.
Affiliations
  • Rossy Cancer Network (CA)
  • McGill University Health Centre (CA)
  • Institut du cancer de Montréal (CA)
  • Jewish General Hospital (CA)
  • McGill University (CA)
Corresponding author
  • Piccirillo, Ciriaco A.
  • Miller, Wilson H.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-10-17
Volume
10
Issue
1
Pages
4712-4712
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-12628-1
PMC
PMC6797722
OpenAlex
W2980830192
Semantic Scholar
0d5ee60a98af0e9647f33716493040110ef44e63
Cited by
109
References
45
Citations by year
2026: 8 · 2025: 6 · 2024: 18 · 2023: 13 · 2022: 19 · 2021: 23 · 2020: 19 · 2019: 3
FWCI
6.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • McGill University Health Centre
  • Jewish General Hospital
  • Fondation de l'Hôpital général juif
  • Canadian Institutes of Health Research (148821_1)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
  • Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
Keywords
mTOR signaling, rapamycin, anti-PD-1 therapy, immune checkpoint inhibitors, kidney transplantation, allograft rejection, allograft tolerance, regulatory T cells, cytotoxic T lymphocytes, eosinophilia, IL-5, eotaxin, interferon-gamma, melanoma
MeSH terms
Female, Graft Rejection, Humans, Immunosuppressive Agents, Kidney Failure, Chronic, Melanoma, Middle Aged, T-Lymphocytes, Cytotoxic, Signal Transduction, Kidney Transplantation, Sirolimus, Transplantation Tolerance, T-Lymphocytes, Regulatory, TOR Serine-Threonine Kinases, Programmed Cell Death 1 Receptor

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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