Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically “cold” tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti–programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8 + T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment.

中文翻译：

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SRC 激酶 HCK 的治疗性抑制促进 T 细胞肿瘤浸润并改善对免疫疗法的反应

尽管免疫疗法彻底改变了癌症治疗，但许多免疫原性肿瘤仍然难以治疗。这在很大程度上归因于免疫学“冷”肿瘤微环境，其特征是免疫抑制性骨髓细胞的积累和活化 T 细胞的排除。在这里，我们证明骨髓特异性造血细胞激酶 (HCK) 的基因消融或治疗性抑制能够在其他方面实现拮抗性抗程序性细胞死亡蛋白 1（抗 PD1）、抗 CTLA4 或激动性抗 CD40 免疫疗法的活性难治性肿瘤并增强对治疗敏感的肿瘤的反应。从机制上讲，HCK 消融将肿瘤相关巨噬细胞和树突状细胞重新编程为炎症内型并增强 CD8+与小鼠免疫疗法结合时的 T 细胞募集和激活。同时，在移植了源自患者的异种移植物的人源化小鼠中，治疗性抑制 HCK 可抵消肿瘤免疫抑制，改善 T 细胞募集，并损害肿瘤生长。总的来说，我们的结果表明，HCK 活性的治疗靶向通过同时刺激免疫细胞活化和抑制免疫抑制性肿瘤微环境来增强对免疫疗法的反应。