Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures
Chester J. Kao, … , Won Jin Ho, Mark Yarchoan
Chester J. Kao, … , Won Jin Ho, Mark Yarchoan
Published October 15, 2024
Citation Information: J Clin Invest. 2024;134(20):e176567. https://doi.org/10.1172/JCI176567.
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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 3

Early changes in T helper–associated cytokines precede grade ≥ 2 irAE development.

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Early changes in T helper–associated cytokines precede grade ≥ 2 irAE de...
(A) Schema for early on-treatment time event analysis (n = 88). (B) Scatterplot displaying the adjusted HR for early on-treatment cytokine fold change and time to onset of grade ≥ 2 irAEs utilizing a multivariate Cox model and multitesting adjustment. The dotted line represents unadjusted P = 0.05, in which cytokines above the line are significant without multitesting correction. The size of each cytokine dot represents the width of the 95% CI range. (C–H) Reverse Kaplan-Meier (KM) plots for cumulative probability of grade ≥ 2 irAEs for statistically significant cytokines from the multivariate Cox model after multitesting adjustment. Optimal cutoffs were determined using maximally selected log-rank statistics. (I) Reverse KM plot for the cumulative probability of grade ≥ 2 irAEs utilizing a combined cytokine status based on presence of high cytokine fold changes as determined by the optimal cutoffs calculated for the 6 cytokines: low, 0-1 cytokines; intermediate, 2-3 cytokines; and high, ≥4 cytokines. Time to irAE onset or last follow up was adjusted for time to early on-treatment sample collection to account for immortal time bias. adj., adjusted; CI, confidence interval; Gr≥2, grade ≥2; HR, hazard ratio; KM, Kaplan Meier.