卵巢癌是女性中第十一种最常见的癌症，也是癌症相关死亡的一个重要原因，带来了相当大的挑战。虽然 Myc 癌基因与多种癌症有关，但它在免疫治疗过程中对表达 Myc 的肿瘤的影响仍然是个谜。我们的研究调查了小鼠卵巢癌细胞系中 Myc 的过度表达，重点关注 HIF1a 功能的改变。利用海马实验来验证 Myc 过度表达后的代谢变化。此外，我们通过使用 Gpr132-/- 小鼠探索与 Myc 过表达肿瘤细胞共培养后的巨噬细胞极化和免疫抑制潜力，以获得机制见解。体内实验建立了具有免疫活性的荷瘤小鼠模型，并通过流式细胞术评估了 Myc 过表达后的 CD8 T 细胞、Treg 和巨噬细胞浸润。此外，还进行了 OTI CD8 T 细胞的过继转移，以研究 Myc 过度表达后抗原特异性免疫反应的变化。研究结果揭示了 HIF1a 降解的显着延迟，增强了其功能并促进了 Myc 过度表达的经典 Warburg 效应。 Myc 过表达肿瘤细胞分泌的乳酸促进 Gpr132 依赖性 M2 巨噬细胞极化，从而诱导巨噬细胞能够显着抑制 CD8 T 细胞功能。值得注意的是，Myc 过表达后肿瘤微环境中的巨噬细胞浸润增加，同时 CD8 T 细胞浸润和功能受损。有趣的是，当向 Gpr132-/- 小鼠施用 Myc 过度表达的肿瘤细胞时，CD4 T 细胞浸润保持不变，并且免疫抑制作用得到减轻，这揭示了卵巢癌管理的潜在治疗途径。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Ovarian cancer, the eleventh most prevalent cancer among women and a significant cause of cancer-related mortality, poses considerable challenges. While the Myc oncogene is implicated in diverse cancers, its impact on tumours expressing Myc during immune therapy processes remains enigmatic. Our study investigated Myc overexpression in a murine ovarian cancer cell line, focusing on alterations in HIF1a function. Seahorse experiments were utilized to validate metabolic shifts post-Myc overexpression. Moreover, we explored macrophage polarization and immunosuppressive potential following coculture with Myc-overexpressing tumour cells by employing Gpr132-/- mice to obtain mechanistic insights. In vivo experiments established an immune-competent tumour-bearing mouse model, and CD8 T cell, Treg, and macrophage infiltration post-Myc overexpression were evaluated via flow cytometry. Additionally, adoptive transfer of OTI CD8 T cells was conducted to investigate antigen-specific immune response variations after Myc overexpression. The findings revealed a noteworthy delay in HIF1a degradation, enhancing its functionality and promoting the classical Warburg effect upon Myc overexpression. Lactic acid secretion by Myc-overexpressing tumour cells promoted Gpr132-dependent M2 macrophage polarization, leading to the induction of macrophages capable of significantly suppressing CD8 T cell function. Remarkably, heightened macrophage infiltration in tumour microenvironments post-Myc overexpression was observed alongside impaired CD8 T cell infiltration and function. Interestingly, CD4 T-cell infiltration remained unaltered, and immune-suppressive effects were alleviated when Myc-overexpressing tumour cells were administered to Gpr132-/- mice, shedding light on potential therapeutic avenues for ovarian cancer management.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.