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Caterina Scirgolea, et al.
DOI: 10.1038/s41590-024-01923-9
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Expansion of antigen-experienced CD8+ T cells is critical for the success of tumor-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. They demonstrated that PGE2 produced by cyclooxygenase (COX) activity in tumor cells does not impair the priming of naïve CD8+ T cells in tumor-draining lymph nodes. In contrast, PGE2 exerts a local role in the tumor microenvironment, selectively targeting TCF1+CD8+ TIL and restricting its expansion and differentiation into effector T cells. This inhibition is mediated by signaling of the PGE2 receptors EP2 and EP4 (EP2/EP4) expressed on CD8+ T cells. Using single-cell RNA sequencing and TCR sequencing, the authors provide a comprehensive overview of the CD8+ TIL population and its developmental trajectory within tumors. They revealed that TCF1+CD8+ TIL could not be clonally amplified and differentiated into effector populations expressing TIM-3 and CXCR6 in the presence of PGE2. Notably, gene knockout of EP2/EP4 signaling in CD8+ T cells rescued this defect, leading to robust amplification and effector differentiation of TCF1+ TIL, ultimately leading to tumor elimination in multiple mouse cancer models. Mechanistically, the authors found that PGE2–EP2/EP4 signaling inhibits TCF1+ TIL responsiveness to IL-2, a key cytokine for T cell expansion and effector differentiation. PGE2 exposure impairs IL-2 receptor expression and downstream signaling pathways, including STAT5 phosphorylation and mTORC1 activation, in TCF1+CD8+ T cells. Restoration of IL-2 responsiveness by inhibition of EP2/EP4 signaling is sufficient to rescue the expansion and effector differentiation of TCF1+ TIL within tumors without compromising its stem-cell-like properties. The study further demonstrated that EP2/EP4-deficient tumor antigen-specific CD8+ T cells undergo clonal expansion and differentiation within the tumor, resulting in the generation of potent effector populations that mediate tumor elimination. This protective anticancer response is abrogated upon blockade of IL-2 receptor signaling, highlighting the critical role of IL-2 reactivity in driving the amplification and effector differentiation of TCF1+ TIL. Overall, this work reveals a previously unrecognized mechanism by which tumor-derived PGE2 limits the anticancer potential of TCF1+CD8+ TIL by inhibiting IL-2 responsiveness. By identifying the PGE2–EP2/EP4 axis as a molecular target, this study provides a theoretical basis for improving T-cell immunotherapy in patients with tumors with high PGE2 expression.
DOI: 10.1038/s41586-024-07352-w
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