Immune checkpoint inhibitors (ICI)such as anti-PD-1 antibody have transformed the treatment for various malignancies. However, dichotomous response profile, unconventional patterns of response such as pseudo-progression, potentially life-threatening immune-mediated toxicities, and very high cost indicate a critical need for robust predictive biomarkers. Serial tumor biopsies would be ideal to evaluate evolution of the tumor and microenvironment during ICI therapy; however, it is challenging for visceral tumors. Discovery of mechanism-driven peripheral blood (PB) biomarkers that correlate with response in early on-treatment will markedly improve current treatment regimens. Emerging evidence has shown that an early on-treatment decrease in PB interleukin 6 (IL-6)levels is associated with response to ICI although the source of IL-6 remains unclear. Excitingly, we have identified a subset of PB T cells spontaneously producing IL-6, and our preliminary data show that early on-treatment change in the frequency of IL-6+T cells correlates with response to anti-PD-1 therapy and better prognosis in patients with various cancers. These findings support the overall hypothesis that changes in the frequency of PB IL-6+ T cells will predict treatment activity early on-treatment in melanoma patients undergoing anti-PD-1 therapy. Aim 1 will test the hypothesis that early on-treatment change of PB IL-6+T cells predicts response to anti-PD-1 therapy in melanoma patients. Aim 2will rigorously characterize the phenotype and function of PB IL-6+T cells.

Our contribution here is expected to address gaps in our knowledge of changes in systemic T-cell immunity during ICI therapy, and yield insights into the less-invasive, repeatable, PB biomarkers. Such an understanding will provide a solid foundation for future development of clinical trials with large cohorts of patients undergoing ICI therapy not only for melanoma, but also for a wide variety of malignancies, and ultimately, for the establishment of more useful immune monitoring strategy.

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