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The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells., Competing Interests: Disclosures:   K. Tsai reported personal fees from Regeneron, grants from Array/Pfizer, grants from Replimune, and grants from Oncosec outside the submitted work. M. Rosenblum reported other from TRex Bio and other from Sitryx Bio outside the submitted work. A. Daud reported grants from Merck, grants from BMS, other from Trex, grants from Pfizer, grants from Incyte, grants from Xencor, grants from Roche, and grants from Novartis during the conduct of the study as well as grants from Oncosec outside the submitted work. A. Sharpe reported grants from NIH R01 CA229851, grants from NIH U54 CA224088, grants from NIH P01 56299, and grants from NIH P01 39671 during the conduct of the study; personal fees from Surface Oncology, personal fees from Sqz Biotech, personal fees from Selecta, personal fees from Monopteros, personal fees from Elstar, personal fees from Elpiscience, grants from Novartis, grants from Roche, grants from Merck, grants from Ipsen, grants from UCB, and grants from Quark Ventures outside the submitted work. In addition, A. Sharpe had a patent number 7,432,059 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis), a patent number 7,722,868 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis), a patent number 8,652,465 licensed (Roche), a patent number 9,457,080 licensed (Roche), a patent number 9,683,048 licensed (Novartis), a patent number 9,815,898 licensed (Novartis), a patent number 9,845,356 licensed (Novartis), a patent number 10,202,454 licensed (Novartis), a patent number 10,457,733 licensed (Novartis), a patent number 9,580,684 issued (none), a patent number 9,988,452 issued (none), and a patent number 10,370,446 issued (none); A. Sharpe is on the scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and is a scientific editor for the Journal of Experimental Medicine. M. Singer reported personal fees from Guardant Health outside the submitted work. No other disclosures were reported., (© 2021 Pauken et al.)

Studies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg PO bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1-positive tumors were enrolled. No objective responses were observed, and accrual was stopped. Stable disease was noted in six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis-generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (T ex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating T ex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

In light of increased cancer prevalence and cancer-specific deaths in patients with infections, we investigated whether infections alter anti-tumor immune responses. We report that acute influenza infection of the lung promotes distal melanoma growth in the dermis and leads to accelerated cancer-specific host death. Furthermore, we show that during influenza infection, anti-melanoma CD8 + T cells are shunted from the tumor to the infection site, where they express high levels of the inhibitory receptor programmed cell death protein 1 (PD-1). Immunotherapy to block PD-1 reverses this loss of anti-tumor CD8 + T cells from the tumor and decreases infection-induced tumor growth. Our findings show that acute non-oncogenic infection can promote cancer growth, raising concerns regarding acute viral illness sequelae. They also suggest an unexpected role for PD-1 blockade in cancer immunotherapy and provide insight into the immune response when faced with concomitant challenges., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)