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

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 (p<0.05). Elevated on-treatment IL-6 was also associated with non-ERs (p<0.05). High baseline IL-17F and IL-23 were associated with superior PFS, and high baseline IL-8 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), 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.

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Publication Details

Journal
Cancer Immunology Research
Published
2026-06-26
DOI
https://doi.org/10.1158/2326-6066.cir-25-1611
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
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article

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

Soren Charmsaz, Daniel J. Zabransky, Waqar Arif, Rajat Mohindra et al.
Cancer Immunology Research
Cancer Immunotherapy and Biomarkers
article

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

Soren Charmsaz, Daniel J. Zabransky, Waqar Arif, Rajat Mohindra, Evan J. Lipson, Mari Nakazawa, Royce P. Lee, Marina Baretti, Christopher J. Thoburn, Madelena Brancati, Chester Kao, Carlotta Pazzi, Xiyu Zhao, Jean Hoffman‐Censits, Won Jin Ho, Nicole Groß, Elizabeth M. Jaffee, Aditi Guha, Hui Li, Yasser Ged, James M. Leatherman, Mark Yarchoan, G. Scott Chandler, Laura Tang, Sanjay Bansal, Jeric P. Hernandez, Caroline Ellis
article en

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 (p<0.05). Elevated on-treatment IL-6 was also associated with non-ERs (p<0.05). High baseline IL-17F and IL-23 were associated with superior PFS, and high baseline IL-8 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), 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.

Cancer Immunology Research
Roche (Switzerland) (CH), Johns Hopkins University (US), Johns Hopkins Medicine (US), Johns Hopkins University Applied Physics Laboratory (US), Kaiser Permanente San Francisco Medical Center (US), Kaiser Permanente South San Francisco Medical Center (US), Johns Hopkins Hospital (US), Sidney Kimmel Comprehensive Cancer Center (US)
Openalex Percentile: Top 8%
Cancer Immunotherapy and Biomarkers
DOISourceOpenAlex
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