Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma

Granier, Clémence; Dariane, C.; Combe, Pierre; Verkarre, Virginie; Urien, Saı̈k; Badoual, Cécile; Roussel, H.; Mandavit, Marion; Ravel, Patrice; Sibony, Mathilde; Biard, Lucie; Radulescu, C.; Vinatier, Emeline; Benhamouda, Nadine; Peyromaure, Michaël; Oudard, Stéphane; Méjean, Arnaud; Timsit, Marc Olivier; Gey, Alain; Tartour, Éric

doi:10.1158/0008-5472.can-16-0274

Cited by 171 publications

(114 citation statements)

References 34 publications

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“…Our trial to reveal prognostic biomarkers in gastrointestinal malignant ascites patients based on T-cell immune phenotyping in multivariate analysis proposed the significance of PD-1+ TIM-3+ascites TILs. These findings are consistent with the finding that existence of PD-1+ TIM-3+ cells was associated with poor prognosis in renal cell carcinoma 12.…”

supporting

confidence: 92%

PD‐1+ TIM‐3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer

et al. 2018

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The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor‐infiltrating lymphocytes (TILs) can predict prognosis in multiple malignancies, including the response to immune checkpoint inhibitors, a breakthrough cancer therapy. However, TILs’ profiles from malignant ascites have not been extensively studied. Using flow cytometric analysis, we quantified the proportion of exhausted T cells and memory/naive/effector T‐cell subsets, among the CD4+ and CD8+ T‐cell populations of paired TILs and peripheral blood T cell samples (n = 22). The correlation between CD4+ and CD8+ subset profiles suggested that the combined analysis of CD4+ and CD8+ cells in malignant ascites was clinically significant. We found that cells positive for the exhaustion markers programmed cell death‐1 (PD‐1), and T‐cell immunoglobulin and mucin domain 3 (TIM‐3), and cells coexpressing PD‐1 and TIM‐3 abundantly exist among malignant ascites TILs. Furthermore, patients with high frequency of PD‐1+ TIM‐3+ cells among the CD4+ and CD8+ T‐cell population showed worse clinical outcome in multivariate analysis (n = 27). We propose that exhausted ascites TILs represent a clinically significant prognostic biomarker in advanced gastrointestinal cancer and represent an important target for immune checkpoint inhibitors.

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confidence: 92%

PD‐1+ TIM‐3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer

et al. 2018

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“…23 The opposite effect is seen in a number of other diseases, such as renal cell carcinoma 25 or nasopharyngeal cancer, 26 where PD-1 expression is associated with a poor outcome. Tim-3 coexpression, which in combination with PD-1 is a marker of T-cell exhaustion, may differentiate between functionally exhausted or activated T lymphocytes 27 and could possibly clarify these discrepancies.…”

Section: Discussionmentioning

confidence: 99%

The PD‐1 and PD‐L1 pathway in recurrent respiratory papillomatosis

et al. 2017

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Objectives/Hypothesis: Generation of an immunosuppressive microenvironment may enable a persistent human papillomavirus infection in the setting of an otherwise normal immune system. We hypothesized that expression of the T-lymphocyte co-inhibitory receptor programmed death 1 (PD-1) and its ligand PD-L1 would be increased in the recurrent respiratory papillomatosis (RRP) microenvironment compared to normal controls.Study Design: Case-control study.Methods: Formalin-fixed paraffin-embedded respiratory papilloma and normal controls were obtained under institutional review board approval, stained for CD4, CD8, FoxP3, and PD-1, and scored by automated cell count. PD-L1 staining was scored by a blinded pathologist using an adjusted inflammation score that accounted for epithelial and immune infiltrate.Results: Thirty-nine RRP cases and seven controls were studied. All immunologic markers demonstrated significantly increased staining in RRP specimens compared to normal controls (all P < .01). PD-1 correlated with both CD4 (P < .0001) and CD8 (P < .001) cell counts. Epithelial staining for PD-L1 (68%) and PD-L11 infiltrating immune cells (76%) were observed in the majority of papilloma samples. The strongest staining for PD-L1 was usually observed in the basal papilloma layer adjacent to the immunologic infiltrate in the vascular core. Disease severity inversely correlated with CD8 cell counts (P 5 .01). A correlation between disease severity and other immunologic markers was not observed.Conclusions: Most RRP specimens demonstrate PD-1 T-lymphocyte infiltration and PD-L1 expression on both papilloma and infiltrating immune cells. This study suggests that this checkpoint pathway may be contributing to local immunosuppression in RRP, and opens the door for clinical trials utilizing PD-blocking monoclonal antibodies.

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“…In line with these results, after infection in mucosal tissues, T RM cells can proliferate and generate a second pool of T RM , strongly suggesting that they have the ability to be activated in situ for better control of local danger [94]. Therefore, their exhausted phenotype does not preclude their sensitivity to reactivation and invigoration [95]. Consistently, recent results revealed expansion of T RM cells in melanoma patients responding to anti-PD-1 immunotherapy [96].…”

Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 94%

Resident memory T cells, critical components in tumor immunology

Mami‐Chouaib¹,

Blanc²,

Corgnac³

et al. 2018

j. immunotherapy cancer

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CD8+ T lymphocytes are the major anti-tumor effector cells. Most cancer immunotherapeutic approaches seek to amplify cytotoxic T lymphocytes (CTL) specific to malignant cells. A recently identified subpopulation of memory CD8+ T cells, named tissue-resident memory T (TRM) cells, persists in peripheral tissues and does not recirculate. This T-cell subset is considered an independent memory T-cell lineage with a specific profile of transcription factors, including Runx3+, Notch+, Hobit+, Blimp1+, BATF+, AHR+, EOMESneg and Tbetlow. It is defined by expression of CD103 (αE(CD103)β7) and CD49a (VLA-1 or α1β1) integrins and C-type lectin CD69, which are most likely involved in retention of TRM cells in non-lymphoid tissues, including solid tumors. CD103 binds to the epithelial cell marker E-cadherin, thereby favoring the location and retention of TRM in epithelial tumor regions in close contact with malignant cells. The CD103-E-cadherin interaction is required for polarized exocytosis of lytic granules, in particular, when ICAM-1 expression on cancer cells is missing, leading to target cell death. TRM cells also express high levels of granzyme B, IFNγ and TNFα, supporting their cytotoxic features. Moreover, the local route of immunization targeting tissue dendritic cells (DC), and the presence of environmental factors (i.e. TGF-β, IL-33 and IL-15), promote differentiation of this T-cell subtype. In both spontaneous tumor models and engrafted tumors, natural TRM cells or cancer-vaccine-induced TRM directly control tumor growth. In line with these results, TRM infiltration into various human cancers, including lung cancer, are correlated with better clinical outcome in both univariate and multivariate analyses independently of CD8+ T cells. TRM cells also predominantly express checkpoint receptors such as PD-1, CTLA-4 and Tim-3. Blockade of PD-1 with neutralizing antibodies on TRM cells isolated from human lung cancer promotes cytolytic activity toward autologous tumor cells. Thus, TRM cells appear to represent important components in tumor immune surveillance. Their induction by cancer vaccines or other immunotherapeutic approaches may be critical for the success of these treatments. Several arguments, such as their close contact with tumor cells, dominant expression of checkpoint receptors and their recognition of cancer cells, strongly suggest that they may be involved in the success of immune checkpoint inhibitors in various cancers.

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Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma

Cited by 171 publications

References 34 publications

PD‐1+ TIM‐3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer

PD‐1+ TIM‐3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer

The PD‐1 and PD‐L1 pathway in recurrent respiratory papillomatosis

Resident memory T cells, critical components in tumor immunology

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