肿瘤细胞治疗研究
英文原题：Dasatinib Remodels the Tumor Microenvironment and Sensitizes Small Cell Lung Cancer to Immunotherapy.
将Dasa与免疫疗法联合使用代表了一种治疗SCLC的策略，其中CCL5作为一种细胞因子，可用于监测治疗反应。
目的：需要有效的策略来重新激活免疫系统，以改善小细胞肺癌（SCLC）的结局。使用达沙替尼（Dasa）靶向Src家族激酶可在某些癌症类型中引发免疫调节效应。在本研究中，我们探索了在SCLC中将Dasa与免疫检查点阻断联合使用的潜力。尽管SCLC模型对抗PD-1或抗CTLA-4治疗无效，但Dasa与免疫治疗联合代表了一种治疗SCLC的策略，其中CCL5可作为一种用于监测反应的细胞因子。意义：多激酶抑制剂与免疫检查点阻断联合治疗通过激活CCL5并共刺激CD4+ T细胞、NK细胞和MHC-II+细胞，克服小细胞肺癌中的免疫抑制性肿瘤微环境。
UNLABELLED: Effective strategies to reinvigorate the immune system are needed to improve outcomes in small cell lung cancer (SCLC). Targeting Src family kinases with dasatinib (Dasa) can elicit immunomodulatory effects in some cancer types. In this study, we explored the potential of combining Dasa with immune checkpoint blockade in SCLC. Although the SCLC models were refractory to anti-PD-1 or anti-CTLA4 monotherapy, anti-PD-1 and anti-CTLA4 combination immunotherapy (ITc) induced a significant antitumor response. Furthermore, the Dasa + ITc combination was superior to ITc or Dasa alone. Dasa + ITc activity was mediated by CD4+ T cells, MHC-II+ antigen-presenting cells, and NK cells, as depletion of these populations impeded the combination treatment antitumor efficacy. Increased tumor infiltration of CD4+ and CD8+ T cells, NK cells, M1-like macrophages, and CD11c+ antigen-presenting cells and a reduction of regulatory T cells and M2-like macrophages were found in Dasa + ITc-treated mice. Dasa increased CCL5 in NK cells and reduced regulatory T-cell conversion from CD4+ lymphocytes. Dasa + ITc therapy elicited robust antitumor efficacy in three-dimensional cocultures of immune and SCLC cells. In vivo experiments showed that CCL5 was necessary for the Dasa + ITc response. In immunotherapy-treated patients with SCLC, a gene signature including CD4, CIITA, and tumor mutational burden predicted good prognosis. On-treatment CCL5 plasma levels were increased only in patients with long progression-free survival, and pretreatment secretomics identified cytokines related to myeloid cells significantly associated with poor prognosis. In summary, combining Dasa with immunotherapy represents a strategy to treat SCLC, with CCL5 as a cytokine that could serve to monitor response. SIGNIFICANCE: Multikinase inhibitor and immune checkpoint blockade combination therapy overcomes the immunosuppressive tumor microenvironment in small cell lung cancer by activating CCL5 and costimulating CD4+ T cells, NK cells, and MHC-II+ cells.
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