Simon S, Voillet V, Vignard V, Wu Z, Dabrowski C, Jouand N, Beauvais T, Khammari A, Braudeau C, Josien R, Adotevi O, Laheurte C, Aubin F, Nardin C, Rulli S, Gottardo R, Ramchurren N, Cheever M, Fling SP, Church CD, Nghiem P, Dreno B, Riddell SR, and Labarriere N
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., Competing Interests: Competing interests: SRR has served as an advisor and has patents licensed to Juno Therapeutics, a Celgene/Bristol-Myers Squibb company; is a founder and employee of Lyell Immunopharma; and has served on advisory boards for Adaptive Biotechnologies and Nohla. PN serves as a paid consultant for EMD Serono. Bristol Myers Squibb has provided research support to PN’s institution. RG has received consulting income from Juno Therapeutics, Takeda, Infotech Soft, Celgene, has received research support from Janssen Pharmaceuticals and Juno Therapeutics, and declares ownership in Cellspace Biosciences. SR and ZW are employed by QIAGEN, however, the studies were conducted in the absence of any potential conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)