Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures
Chester J. Kao, et al.
Chester J. Kao, et al.
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Clinical Medicine Oncology

Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures

Abstract

BACKGROUND Immune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational treatment and interception strategies.METHODS In an observational study, we prospectively collected blood samples and performed regular clinical evaluations for irAEs in patients receiving ICI therapy as standard of care for solid tumors. We performed in-parallel analysis of cytokines by Luminex immunoassay and circulating immune cells by cytometry by time-of-flight (CyTOF) at baseline and on treatment to investigate mechanisms of irAEs.RESULTS We enrolled 111 patients, of whom 40.5% developed a symptomatic irAE (grade ≥ 2). Development of a grade ≥ 2 irAE was positively associated with the use of combination ICI and a history of an autoimmune disorder. Early changes in T helper 17 (Th17) (IL-6, IL-17f), type 2 (IL-5, IL-13, IL-25), and type 1 (TNF-α) cytokine signatures and congruent on-treatment expansions of Th17 and Th2 effector memory (Th2EM) T cell populations in peripheral blood were positively associated with the development of grade ≥2 irAEs. IL-6 levels were also associated with inferior cancer-specific survival and overall survival.CONCLUSIONS In a diverse, prospective pan-tumor cohort, Th17 and Th2 skewing during early ICI treatment was associated with the development of clinically relevant irAEs but not antitumor responses, providing possible targets for monitoring and therapeutic interventions.FUNDING Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the NCI SPORE in Gastrointestinal Cancers (P50 CA062924), NCI grant (R50CA243627 to LD), the NIH Center Core Grant (P30 CA006973), Swim Across America (to MY), NIAMS (K23AR075872 to LC), and imCORE-Genentech grant 137515 (to Johns Hopkins Medicine on behalf of MY).

Authors

Chester J. Kao, Soren Charmsaz, Stephanie L. Alden, Madelena Brancati, Howard L. Li, Aanika Balaji, Kabeer Munjal, Kathryn Howe, Sarah Mitchell, James Leatherman, Ervin Griffin, Mari Nakazawa, Hua-Ling Tsai, Ludmila Danilova, Chris Thoburn, Jennifer Gizzi, Nicole E. Gross, Alexei Hernandez, Erin M. Coyne, Sarah M. Shin, Jayalaxmi Suresh Babu, George W. Apostol, Jennifer Durham, Brian J. Christmas, Maximilian F. Konig, Evan J. Lipson, Jarushka Naidoo, Laura C. Cappelli, Aliyah Pabani, Yasser Ged, Marina Baretti, Julie Brahmer, Jean Hoffman-Censits, Tanguy Y. Seiwert, Rachel Garonce-Hediger, Aditi Guha, Sanjay Bansal, Laura Tang, Elizabeth M. Jaffee, G. Scott Chandler, Rajat Mohindra, Won Jin Ho, Mark Yarchoan

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Figure 6

Higher early treatment changes in IL-6 are associated with worse cancer-specific and overall survival.

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Higher early treatment changes in IL-6 are associated with worse cancer-...
From the multivariate Cox models for the early on-treatment cohort (n = 88), scatterplots displaying log10 transformed adjusted HRs for early on-treatment cytokine fold changes and the time to grade ≥ 2 irAE onset compared with (A) cancer-specific survival and (B) overall survival. Cytokines that are significant after FDR adjustment are displayed. (C) Cancer-specific survival and (D) overall survival KM curves stratified by an optimal fold change cutoff of 2.3 for early treatment changes in IL-6. The optimal cutoff was determined using maximally selected log-rank statistics. (E) Landmark analysis at 10 weeks stratified by optimal fold change cutoff of 2.3 for early treatment changes in IL-6 and grade ≥ 2 irAE development. For landmark analyses, grade ≥ 2 irAEs had to occur prior to the landmark time. Significance for KM curves was assessed utilizing log-rank test. FDR, false discovery rate; Gr≥2, grade ≥ 2; HR, hazard ratio; KM, Kaplan Meier.