Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) in vitro in the microsatellite-stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. In vivo, the combination was able to induce ICD, but not the single agents, although all treatment groups showed T-cell dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells or myeloid-derived suppressor cells but eliminated type-2 tumor-associated macrophages (TAM2), resulting in higher cytotoxic CD8+ T-cell infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8+ T cells, leading to secondary T-cell exhaustion. Finally, although anti-PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti-PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD in vivo, providing a rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in patients with metastatic colorectal cancer.

中文翻译：

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Trifluridine / Tipiracil加上Oxaliplatin通过诱导免疫原性细胞死亡和消耗巨噬细胞来改善结直肠癌的PD-1阻断作用。

三氟吡啶/替普拉西酯（FTD / TPI）是一种新的抗代谢药物，用于治疗化学难治性转移性结直肠癌。FTD / TPI在微卫星稳定（MSS）CT26小鼠结肠癌细胞系以及各种人类MSS结直肠癌细胞系（SW620，Caco-2和Colo-320）中体外诱导免疫原性细胞死亡（ICD） 。FTD / TPI与奥沙利铂的组合可协同促进ICD。在体内，尽管所有治疗组均显示出T细胞依赖性，但该组合物能够诱导ICD，但不能诱导单一药物。此外，FTD / TPI和奥沙利铂不影响调节性T细胞或髓样来源的抑制细胞，但消除了2型肿瘤相关巨噬细胞（TAM2），从而导致更高的细胞毒性CD8 + T细胞浸润和激活。该效应与肿瘤细胞上PD-L1表达和CD8 + T细胞上PD-1诱导相关，导致继发性T细胞衰竭。最后，尽管抗PD-1无法与FTD / TPI或奥沙利铂单一疗法协同作用，但将抗PD-1与FTD / TPI和奥沙利铂同时给药可增强双重化疗的抗肿瘤功效。我们的研究显示FTD / TPI和奥沙利铂在消耗TAM2方面具有新型免疫调节作用。奥沙利铂和FTD / TPI的组合在体内诱导了ICD，为使用这些药物消除转移性结直肠癌患者的免疫抑制细胞和提高检查点效力提供了理论依据。尽管抗PD-1无法与FTD / TPI或奥沙利铂单一疗法协同作用，但将抗PD-1与FTD / TPI和奥沙利铂同时给药可增强双重化疗的抗肿瘤功效。我们的研究显示FTD / TPI和奥沙利铂在消耗TAM2方面具有新型免疫调节作用。奥沙利铂和FTD / TPI的组合在体内诱导了ICD，为使用这些药物消除转移性结直肠癌患者的免疫抑制细胞和提高检查点效力提供了理论依据。尽管抗PD-1无法与FTD / TPI或奥沙利铂单一疗法协同作用，但将抗PD-1与FTD / TPI和奥沙利铂同时给药可增强双重化疗的抗肿瘤功效。我们的研究显示FTD / TPI和奥沙利铂在消耗TAM2方面具有新型免疫调节作用。奥沙利铂和FTD / TPI的组合在体内诱导了ICD，为使用这些药物消除转移性结直肠癌患者的免疫抑制细胞和提高检查点效力提供了理论依据。