Anti-CTLA4 Therapy Leads to Early Expansion of a Peripheral Th17 Population and Induction of Th1 Cytokines.

Abstract

The systemic immunologic effects of combining anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapy with PDL1 blockade remain incompletely characterized despite the widespread use of this combination in treating various solid tumors across multiple stages of disease. In this study, we investigated the additive impact of anti-CTLA4 on peripheral immune signatures in patients undergoing PDL1 blockade, using blood samples from a cohort of patients receiving checkpoint inhibitor therapy for advanced solid tumors. We performed in-parallel analysis of peripheral blood mononuclear cells using cytometry by time of flight and plasma cytokines using Luminex immunoassay. Our study cohort included 104 patients: 54 received anti-PDL1 alone and 50 received anti-PDL1 in combination with anti-CTLA4. As compared with single-agent anti-PDL1, combination therapy was associated with a greater expansion of CD4+ Th cell subsets, including Th17 (adjusted P = 0.04) and regulatory T cells (adjusted P = 0.02), after multivariable and multiple testing adjustment. In patients receiving anti-CTLA4, examination of functional marker expression within the Th17 subset revealed an increase in the expression of the Th1-related transcription factor TBET (P = 0.003). Assessment of the peripheral cytokine signatures showed an increase in Th1-associated cytokines (P = 0.002) in recipients of combination anti-PDL1 and anti-CTLA4, particularly the IFNγ-inducible cytokines MIG (adjusted P = 0.05) and IP-10 (adjusted P = 0.05). Our results confirm prior reports that anti-CTLA4 therapy is associated with the augmentation of Th17 cell subsets, and they also show that anti-CTLA4 may reshape CD4+ T-cell responses through Th17-to-Th1 plasticity, revealing a potential mechanism for enhanced antitumor immunity with broader implications for immune modulation in immunotherapy.