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Immunotherapies targeting the PD-1 pathway have profoundly transformed the clinical care of cancer patients for a growing variety of cancer types. However, most patients do not experience durable clinical benefit. The definition of robust and convenient biomarkers of PD-1 therapy efficacy to stratify patients beforehand or early after initiation of the therapy that could guide therapeutic management is still lacking while being a very active research field. Biomarkers described to date include tumor burden, neoantigen load, presence and number of PD-1+ CD8+ at the tumor margin, T-cell inflamed tumor microenvironment and PD-L1 expression by the tumor cells or other immune cells and composition of the gut microbiota. Most of these parameters are closely related/influenced by the presence, activation status and functional capacities of CD8+ T cells infiltrating the tumor site demonstrating their pivotal role for anti-PD-1 mediated anti-tumor efficacy. A population of PD-1high CD8 TILs was consequently described as predictive of PD-1 blockade in NSCLC. The exact contribution for clinical efficacy of TILs versus distinct CD8+ T cells from peripheral origins recirculating to the tumor site remains to be elucidated. Notably, immunological responses to PD-1 blockade at the periphery were described within the very first days following the first therapy dose. Therefore, describing circulating cellular population predictive of PD-1 inhibitor efficacy could represent a convenient, non-invasive and rapid method to assess anti-tumor benefits. Original findings reported in this study identified a circulating CD8 T cell population delineated by the co-expression of TIGIT and PD-1 inhibitory receptors as an early immune marker of anti-PD-1 efficacy in three independent cohorts of cancer patients (two melanoma patient's cohorts and one Merkel-cell carcinoma patient's cohort). The frequency of this double positive (DPOS) population even appeared predictive of PD-1 inhibitor therapy efficacy at baseline in the MCC cohort. Furthermore, to understand the mechanistical relevance of this subset for PD-1 blockade efficacy, we thoroughly described this DPOS T cell subset by flow cytometry, gene expression analysis, anti-tumor reactivity assay and TCR repertoire analysis, and compared it to its double negative (DNEG), PD-1 and TIGIT single positive counterparts. This DPOS subset was enriched in activated and proliferative T cells, retained expression of co-stimulatory molecules and was enriched for common features with Tfc. Moreover, this subpopulation exhibited a specific gene signature, strongly predictive of long-term survival in melanoma patients (TCGA analyses). We demonstrated that this subpopulation was enriched in tumor-specific T-cells (ELISPOT analysis against 11 antigen-derived peptides). Finally, clustering of TCR clonotypes revealed that the DPOS T cell population was significantly enriched in emerging clonotypes in responding patients, after 1 month of anti-PD-1 therapy echoing recent work from others. Our findings provide a compelling rationale to measure PD-1+TIGIT+ CD8 T-cell subset in the blood of cancer patients to monitor early anti-PD1 mediated clinical efficacy, and to use DPOS T cells as a window to study the dynamic changes that underly successful antitumor immunity. Citation Format: Sylvain Simon, Valentin Voillet, Virginie Vignard, Zhong Wu, Camille Dabrowski, Nicolas Jouand, Tiffany Beauvais, Amir Khammari, Cecile Braudeau, Regis Josien, Olivier Adotevi, Caroline Laheurte, Francçois Aubin, Charles Nardin, Samuel Rulli, Raphaël Gottardo, Nirasha Ramchurren, Cheever Martin, Steven P. Fling, Candice D. Church, Paul Nghiem, Brigitte Dreno, Stanley R. Riddell, Nathalie Labarriere. PD-1 and TIGIT co-expression identifies a circulating CD8 T cell population predictive of response to anti-PD-1 therapy in melanoma and Merkel-cell carcinoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4476.