Data from Peripheral Th17 Immune Signature Associates with Excellent Response to Anti–PD-1/Anti–PD-L1 Therapy across Solid Tumors

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Abstract Immune checkpoint inhibitors (ICI) have transformed cancer care, at times generating durable partial response (PR) or even complete response (CR) 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–PD-1 or anti–PD-L1 alone or in combination with other agents. In this cohort, 30 of 124 (24.2%) patients were classified as excellent responders (ER), defined as experiencing a CR or a durable PR with progression-free survival (PFS) ≥1 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, IL17F, IL21, and IL23 and decreased IL8 compared with non-ERs (P < 0.05). Elevated on-treatment IL6 was also associated with non-ERs (P < 0.05). High baseline IL17F and IL23 were associated with superior PFS, and high baseline IL8 was associated with inferior overall survival (P < 0.05). 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 (P < 0.01) that 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.