Recent advances in immune checkpoint inhibition, which augment T-cell immune responses, have highlighted the potential of exploiting one's immune system to combat cancer. However, only a relatively small number of non-small cell lung cancer (NSCLC) patients benefit from immune checkpoint blockade due to the immunosuppressive tumor microenvironment. Therefore, combination immunotherapies are now being developed to achieve maximal therapeutic benefits. In this study, we assessed whether a novel erlotinib derivative, TD-92, which possesses anti-tumor effects across several cancer cell lines, could enhance anti-PD-1 treatment. Our results demonstrated that the combined treatment of anti-PD-1 and TD-92 resulted in a potent anti-tumor response in a Lewis lung carcinoma cancer model, as evidenced by the reduced tumor growth and increased survival. Analysis of immune cell population counts revealed that TD-92 reduced the number of pro-tumorigenic CD11b⁺ F4/80⁺ tumor-associated macrophages, without significantly affecting the total numbers of other major immunocytes. Further experiments showed that TD-92 induced a marked decline in colony stimulating factor 1 receptor (CSF-1R) expression in macrophage cell lines. The results also suggested that c-Cbl-mediated proteasome degradation was involved in TD-92-mediated CSF-1R downregulation. Our data paves the way for the development of additional combination immunotherapies for NSCLC patients.

免疫检查点抑制的最新进展增强了T细胞的免疫反应，突显了利用自身免疫系统对抗癌症的潜力。但是，由于免疫抑制性肿瘤微环境的缘故，只有相对少数的非小细胞肺癌（NSCLC）患者受益于免疫检查点封锁。因此，目前正在开发组合免疫疗法以实现最大的治疗益处。在这项研究中，我们评估了在多种癌细胞系中均具有抗肿瘤作用的新型埃罗替尼衍生物TD-92是否可以增强抗PD-1治疗。我们的结果表明，抗PD-1和TD-92的联合治疗在Lewis肺癌模型中产生了有效的抗肿瘤反应，这可通过减少肿瘤生长和增加生存率来证明。⁺ F4 / 80 ⁺肿瘤相关的巨噬细胞，而不会显着影响其他主要免疫细胞的总数。进一步的实验表明，TD-92诱导巨噬细胞系中集落刺激因子1受体（CSF-1R）表达明显下降。结果还表明，c-Cbl介导的蛋白酶体降解与TD-92介导的CSF-1R下调有关。我们的数据为非小细胞肺癌患者开发其他联合免疫疗法铺平了道路。