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PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy.

ABSTRACT: BACKGROUND:Clinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated. METHODS:We isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets. RESULTS:We documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1?month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response. CONCLUSIONS:Our results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.

SUBMITTER: Simon S

PROVIDER: S-EPMC7668369 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy.

Simon Sylvain S Voillet Valentin V Vignard Virginie V Wu Zhong Z Dabrowski Camille C Jouand Nicolas N Beauvais Tiffany T Khammari Amir A Braudeau Cécile C Josien Régis R Adotevi Olivier O Laheurte Caroline C Aubin François F Nardin Charles C Rulli Samuel S Gottardo Raphael R Ramchurren Nirasha N Cheever Martin M Fling Steven P SP Church Candice D CD Nghiem Paul P Dreno Brigitte B Riddell Stanley R SR Labarriere Nathalie N

Journal for immunotherapy of cancer 20201101 2

<h4>Background</h4>Clinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.<h4>Methods</h4>We isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally afte ...[more]

PMID: 33188038

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Project description:Purpose/objectiveRadiotherapy (RT) induces an immunogenic antitumor response, but also some immunosuppressive barriers. It remains unclear how different fractionation protocols can modulate the immune microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors (ICI) in association with RT. However, only few trials aim to optimize the RT fractionation to improve efficacy of these associations. Here we sought to characterize the effect of different fractionation protocols on immune response with a view to associating them with ICI.Materials/methodsMice bearing subcutaneous CT26 colon tumors were irradiated using a SARRP device according to different radiation schemes with a same biologically effective dose. Mice were monitored for tumor growth. The radiation immune response (lymphoid, myeloid cells, lymphoid cytokines and immune checkpoint targets) was monitored by flow cytometry at different timepoints after treatment and by RNA sequencing analysis (RNAseq). The same radiation protocols were performed with and without inhibitors of immune checkpoints modulated by RT.ResultsIn the absence of ICI, we showed that 18x2Gy and 3x8Gy induced the longest tumor growth delay compared to 1×16.4Gy. While 3x8Gy and 1×16.4Gy induced a lymphoid response (CD8+ T-cells, Regulators T-cells), 18x2Gy induced a myeloid response (myeloid-derived suppressor cells, tumor-associated macrophages 2). The secretion of granzyme B by CD8+ T cells was increased to a greater extent with 3x8Gy. The expression of PD-L1 by tumor cells was moderately increased by RT, but most durably with 18x2Gy. T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression by CD8+ T-cells was increased with 3x8Gy, but decreased with 18x2Gy. These results were also observed with RNAseq. RT was dramatically more effective with 3x8Gy compared to all the other treatments schemes when associated with anti-TIGIT and anti-PD-L1 (9/10 mice in complete response). The association of anti-PD-L1 and RT was also effective in the 18x2Gy group (8/12 mice in complete response).ConclusionEach fractionation scheme induced different lymphoid and myeloid responses as well as various modulations of PD-L1 and TIGIT expression. Furthermore, 3x8Gy was the most effective protocol when associated with anti-PD-L1 and anti-TIGIT. This is the first study combining RT and anti-TIGIT with promising results; further studies are warranted.

Dataset Information

PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy.

Publications

PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy.

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