Peripheral Th17 immune signature associates with excellent response to anti-PD1/anti-PD-L1 therapy across solid tumors

Abstract Immune checkpoint inhibitors (ICIs) have transformed cancer care, at times generating durable partial or even complete responses in advanced cancers. However, only a minority of patients experience these “excellent” responses. Thus, there is a need for novel biomarkers that can identify those with robust clinical benefit. To address this, we prospectively collected blood samples from 124 patients with advanced and/or metastatic pan-solid tumors treated as standard of care with anti-PD1 or anti-PDL1 alone or in combination with other agents. In this cohort, 30 of 124 (24.2%) patients were classified as excellent responders (ERs), defined as experiencing a complete response or a durable partial response with progression-free survival (PFS)  one year. Peripheral immune cells were analyzed by Cytometry by Time-of-Flight and cytokines were analyzed using a multiplex immunoassay. At baseline and early-on-treatment, ERs had elevated concentrations of Th17-associated cytokines, IL-17F, IL-21, and IL-23, and decreased IL-8 compared to non-ERs (p0.05). Elevated on-treatment IL-6 was also associated with non-ERs (p0.05). High baseline IL-17F and IL-23 were associated with superior PFS, and high baseline IL-8 with inferior overall survival (p0.05). Non-ERs demonstrated decreased proportions of Th17 cells from baseline to early-on-treatment. Regression analysis of functional markers in non-ERs showed a proliferation of exhaustion-like Th17 cells (Ki67+TIGIT+) from baseline to early-on-treatment (p0.01), which was not present in ERs. This study identifies the Th17 pathway as a potential correlate of excellent ICI response and represents a comprehensive exploration of peripheral immune signatures associated with durable ICI benefit.