Enhancing the Generation of Eomeshi CD8+ T Cells Augments the Efficacy of OX40- and CTLA-4–Targeted Immunotherapy

癌症研究 免疫疗法 癌症免疫疗法 CD8型 细胞毒性T细胞 免疫系统 T细胞 免疫学 生物 体外 生物化学
作者
Dana A. Emerson,Annah S. Rolig,William L. Redmond
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:9 (4): 430-440 被引量:14
标识
DOI:10.1158/2326-6066.cir-20-0338
摘要

Abstract CTLA-4 blockade in combination with an agonist OX40-specific monoclonal antibody synergizes to augment antitumor immunity through enhanced T-cell effector function, leading to increased survival in preclinical cancer models. We have shown previously that anti-OX40/anti–CTLA-4 combination therapy synergistically enhances the expression of Eomesodermin (Eomes) in CD8+ T cells. Eomes is a critical transcription factor for the differentiation and memory function of CD8+ T cells. We hypothesized that EomeshiCD8+ T cells were necessary for anti-OX40/anti–CTLA-4 immunotherapy efficacy and that further enhancement of this population would improve tumor-free survival. Indeed, CD8+ T cell–specific deletion of Eomes abrogated the efficacy of anti-OX40/anti–CTLA-4 therapy. We also found that anti-OX40/anti–CTLA-4–induced EomeshiCD8+ T cells expressed lower levels of checkpoint receptors (PD1, Tim-3, and Lag-3) and higher levels of effector cytokines (IFNγ and TNFα) than their Eomeslo counterparts. Eomes expression is negatively regulated in T cells through interleukin-2–inducible T-cell kinase (ITK) signaling. We investigated the impact of modulating ITK signaling with ibrutinib, an FDA-approved tyrosine kinase inhibitor, and found that anti-OX40/anti–CTLA-4/ibrutinib therapy further enhanced CD8+ T cell–specific Eomes expression, leading to enhanced tumor regression and improved survival, both of which were associated with increased T-cell effector function across multiple tumor models. Taken together, these data demonstrate the potential of anti-OX40/anti–CTLA-4/ibrutinib as a triple therapy to improve the efficacy of immunotherapy.
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