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Published on: February 5, 2020
Peripheral Th17 Immune Signature Associates with Excellent Response to Anti-PD-1/Anti-PD-L1 Therapy across Solid
Howard L Li1,2,3,4, Soren Charmsaz1,3,4, Chester Kao1,3,4
1Sidney Kimmel Comprehensive Cancer Center , Johns Hopkins University (a member of the imCORE Network), Baltimore, Maryland.
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.
Insights
Immune checkpoint inhibitors (ICIs) can lead to excellent responses in cancer patients. This study found that the Th17 immune pathway and specific cytokines are linked to these durable responses, offering potential biomarkers for treatment success.
Area of Science:
- Oncology
- Immunology
- Biomarker Discovery
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but only a subset of patients achieve significant clinical benefit.
- Identifying biomarkers for excellent responses to ICIs is crucial for optimizing patient selection and treatment strategies.
Purpose of the Study:
- To identify peripheral immune cell and cytokine signatures associated with excellent responses to ICI therapy in patients with advanced solid tumors.
- To explore the role of the Th17 pathway in predicting durable clinical benefit from ICIs.
Main Methods:
- Prospective collection of blood samples from 124 patients with advanced solid tumors treated with anti-PD1/anti-PDL1 agents.
- Analysis of peripheral immune cells using Cytometry by Time-of-Flight and cytokines via multiplex immunoassay.
- Classification of patients into excellent responders (ERs) based on complete response or durable partial response (PFS ≥ 1 year).
Main Results:
- Excellent responders (24.2%) exhibited elevated baseline and on-treatment Th17-associated cytokines (IL-17F, IL-21, IL-23) and lower IL-8 compared to non-ERs.
- High baseline IL-17F and IL-23 correlated with superior progression-free survival (PFS), while high IL-8 correlated with inferior overall survival.
- Non-ERs showed a decrease in Th17 cell proportions and a proliferation of exhaustion-like Th17 cells (Ki67+TIGIT+) from baseline to on-treatment.
Conclusions:
- The Th17 immune pathway is a potential correlate of excellent response to ICI therapy.
- Specific cytokine profiles (IL-17F, IL-23, IL-8) and Th17 cell dynamics may serve as predictive biomarkers for ICI efficacy.
- Further research into these peripheral immune signatures could lead to improved patient stratification for cancer immunotherapy.
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