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Background: The need for reliable clinical biomarkers to predict which patients with melanoma will benefit from immune checkpoint blockade (ICB) remains unmet. Several different parameters have been considered in the past, including routine differential blood counts, T cell subset distribution patterns and quantification of peripheral myeloid-derived suppressor cells (MDSC), but none has yet achieved sufficient accuracy for clinical utility., Methods: Here, we investigated potential cellular biomarkers from clinical routine blood counts as well as several myeloid and T cell subsets, using flow cytometry, in two independent cohorts of a total of 141 patients with stage IV M1c melanoma before and during ICB., Results: Elevated baseline frequencies of monocytic MDSCs (M-MDSC) in the blood were confirmed to predict shorter overall survival (OS) (HR 2.086, p=0.030) and progression-free survival (HR 2.425, p=0.001) in the whole patient cohort. However, we identified a subgroup of patients with highly elevated baseline M-MDSC frequencies that fell below a defined cut-off during therapy and found that these patients had a longer OS that was similar to that of patients with low baseline M-MDSC frequencies. Importantly, patients with high M-MDSC frequencies exhibited a skewed baseline distribution of certain other immune cells but these did not influence patient survival, illustrating the paramount utility of MDSC assessment., Conclusion: We confirmed that in general, highly elevated frequencies of peripheral M-MDSC are associated with poorer outcomes of ICB in metastatic melanoma. However, one reason for an imperfect correlation between high baseline MDSCs and outcome for individual patients may be the subgroup of patients identified here, with rapidly decreasing M-MDSCs on therapy, in whom the negative effect of high M-MDSC frequencies was lost. These findings might contribute to developing more reliable predictors of late-stage melanoma response to ICB at the individual patient level. A multifactorial model seeking such markers yielded only MDSC behavior and serum lactate dehydrogenase as predictors of treatment outcome., Competing Interests: Competing interests: TA reports institutional grants from SkylineDx, institutional grants and personal fees from Novartis, institutional grants from NeraCare, personal fees from BMS, institutional grants from Sanofi, personal fees from CeCaVa, personal fees from Pierre Fabre, outside the submitted work. NW reports an advisory role for Pierre Fabre and Sanofi, consultant's honoraria from Novartis, and has received travel support from AbbVie and Amgen outside the submitted work. FM reports receiving commercial research grants from Novartis and Roche; and has received travel support and/or speaker’s fees and/or advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme and Pierre Fabre. PT has received travel support and/or speaker’s fees and/or advisor’s honoraria by Almirall, Biofrontera, Bristol-Myers Squibb, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and 4SC. CG reports receiving commercial research grants from Bristol-Myers Squibb, Novartis and Roche; and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche. GP has received speaker’s honoraria from Novartis, Roche, Pfizer, GlaxoSmithKline and Astellas. TE has received travel support and/or speaker’s fees and/or advisor’s honoraria by Sanofi, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Almiral Hermal and Pierre Fabre. BW reports receiving commercial research grants from, is a consultant/advisory board member for and reports receiving travel reimbursement from Bristol-Myers Squibb and Merck Sharp & Dohme. KW-H received commercial research grants from CatalYm GmbH and travel support from Society for Immunotherapy of Cancer. No potential conflicts of interest were disclosed by the other authors., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Anti-programmed cell death protein 1 (PD-1) antibodies are now routinely administered for metastatic melanoma and for increasing numbers of other cancers, but still only a fraction of patients respond. Better understanding of the modes of action and predictive biomarkers for clinical outcome is urgently required. Cancer rejection is mostly T cell-mediated. We previously showed that the presence of NY-ESO-1-reactive and/or Melan-A-reactive T cells in the blood correlated with prolonged overall survival (OS) of patients with melanoma with a heterogeneous treatment background. Here, we investigated whether such reactive T cells can also be informative for clinical outcomes in metastatic melanoma under PD-1 immune-checkpoint blockade (ICB)., Methods: Peripheral blood T cell stimulation by NY-ESO-1 and Melan-A overlapping peptide libraries was assessed before and during ICB in two independent cohorts of a total of 111 patients with stage IV melanoma. In certain cases, tumor-infiltrating lymphocytes could also be assessed for such responses. These were characterized using intracellular cytokine staining for interferon gamma (IFN-γ), tumor negrosis factor (TNF) and CD107a. Digital pathology analysis was performed to quantify NY-ESO-1 and Melan-A expression by tumors. Endpoints were OS and progression-free survival (PFS)., Results: The initial presence in the circulation of NY-ESO-1- or Melan-A-reactive T cells which became no longer detectable during ICB correlated with validated, prolonged PFS (HR:0.1; p>0.0001) and OS (HR:0.2; p=0.021). An evaluation of melanoma tissue from selected cases suggested a correlation between tumor-resident NY-ESO-1- and Melan-A-reactive T cells and disease control, supporting the notion of a therapy-associated sequestration of cells from the periphery to the tumor predominantly in those patients benefitting from ICB., Conclusions: Our findings suggest a PD-1 blockade-dependent infiltration of melanoma-reactive T cells from the periphery into the tumor and imply that this seminally contributes to effective treatment., Competing Interests: Competing interests: CG reports receiving commercial research grants from Bristol-Myers Squibb, Novartis, and Roche; and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. BW reports receiving commercial research grants from, is a consultant/advisory board member for, and reports receiving travel reimbursement from Bristol-Myers Squibb and Merck Sharp & Dohme. F. Meier reports receiving commercial research grants from Novartis and Roche; and has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LF reported grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma, and Novartis Foundation as well as an advisory role for Novartis, Sanofi, Philogen and Bristol-Myers Squibb. PT has received speaker’s honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Roche, Kyowa Kirin, Biofrontera, consultant’s honoraria from Bristol-Myers Squibb, Merck Serono, Novartis, Sanofi, Kirin Kyowa, and Roche and travel support from Bristol-Myers Squibb and Pierre-Fabre. SF reports receiving speaker’s fees by TAKEDA Pharmaceutical. TE has received speaker’s honoraria from Bristol-Myers Squibb, Novartis, Almiral Hermal, and Roche, consultant’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Pierre Fabre and Roche. TS and HN received a research grant from Novartis. GP has received speaker’s honoraria from Novartis, Roche, GlaxoSmithKline and Astellas. MWL is a co-inventor of several patents owned by Immatics Biotechnologies, and has acted as a consultant and/or advisory board member for Boehringer Ingelheim Pharma Gmbh & Co. KG. HZ is employed by CeGaT GmbH. KW-H received commercial research grants from the CatalYm GmbH and travel support from SITC (Society for Immunotherapy of Cancer). No potential conflicts of interest were disclosed by the other authors. KW-H is the guarantor for this manuscript., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)