KLF2 inhibition expands tumor-resident T cells and enhances tumor immunity

TL;DR

Inhibiting KLF2 in T cells boosts their presence in tumors and improves the immune system's ability to fight cancer.

Contribution

This study shows that inhibiting KLF2 promotes tumor-resident T cell accumulation and directly links these cells to improved tumor immunity.

Findings

KLF2 inhibition in CD8+ T cells increases intratumoral CD69+CD103+ and CD69+CD49a+ cells.

Enhanced tumor control was observed in mice with KLF2-downregulated T cells.

The study confirms that intratumoral CD8+CD69+CD103+ and CD8+CD69+CD49a+ cells are Trm and contribute to tumor immunity.

Abstract

Tissue resident memory CD8+ T cells (Trm) constitute a distinct population of non-circulating memory T cells1–5 vastly exceeding the number of circulating T cells5, and play a pivotal role in protective immunity against pathogens6–8. How to promote the generation of vaccine specific Trm remains an important challenge. Whether Trm contribute also to immune control of tumors or just correlate with an unrelated process linked to clinical outcome has not been unequivocally established9,10, and phenotypic markers such as co-expression of CD69 and CD103 or CD49a integrins commonly used to monitor tumor infiltrating Trm do not unambiguously define this subset. Here we tested the hypothesis that transient downregulation of KLF2, the most conserved feature of Trm ontogeny4,11,12, will promote the differentiation of vaccine activated CD8+ T cells into Trm and enhance antitumor immunity. We show that 4-1BB antibody targeted delivery of a KLF2 siRNA to tumor bearing mice led to the downregulation of KLF2 in vaccine activated CD8+ T cells and the accumulation of phenotypically defined intratumoral CD69+CD103+ and CD69+CD49a+ CD8+ T cells which correlated with enhanced control of tumor growth. This study could serve as the foundation of a broadly applicable and clinically useful way to promote the generation of vaccine specific Trm and provides direct evidence that intratumoral CD8+CD69+CD103+ and CD8+CD69+CD49a+ cells are indeed Trm and that Trm contribute to tumor immunity.

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