在黑色素瘤中，免疫细胞渗透到肿瘤中与患者预后和免疫治疗的反应有关。T细胞非炎性肿瘤（冷肿瘤）与肿瘤细胞内在Wnt/β-连环蛋白激活有关，并且通常对抗PD-1单独或与抗CTLA-4治疗联合治疗具有抗药性。颠倒“冷肿瘤”表型和寻找新的有效免疫疗法是挑战。我们试图研究一种新型免疫疗法药物B7-H3在此情况下的作用。采用RNA测序技术，来自一个明确定义的β-连环蛋白驱动的临床前黑色素瘤模型中，以B7-H3抑制为中心点，发现共同靶向策略。我们发现，免疫检查点分子B7-H3通过调节抗病毒信号和先天免疫来提供抑制性肿瘤微环境。B7-H3抑制导致发炎微环境的产生，并且CD47 / SIRPa信号的上调以及与巨噬细胞检查点CD47的阻断合并，导致了增加的抗肿瘤反应。我们发现，B7-H3 / CD47抗体组合的抗肿瘤效应依赖于细胞因子信号通路（CCR5 / CCL5和IL4）。 © 2023 John Wiley＆Sons A / S。由John Wiley＆Sons Ltd.出版。

In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T-cell non-inflamed tumors (cold tumors) are associated with tumor cell-intrinsic Wnt/β-catenin activation, and are typically resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the 'cold tumor' phenotype and identifying new effective immunotherapies are challenges. We sought to investigate the role of a newer immunotherapy agent, B7-H3, in this setting. RNA sequencing was used to identify co-targeting strategies upon B7-H3 inhibition in a well-defined preclinical melanoma model driven by β-catenin. We found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and innate immunity. B7-H3 inhibition led to an inflamed microenvironment, up-regulation of CD47/SIRPa signaling, and together with blockade of the macrophage checkpoint CD47 resulted in additive antitumor responses. We found that the antitumor effects of the B7-H3/CD47 antibody combination were dependent on cytokine signaling pathways (CCR5/CCL5 and IL4).© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.