尽管检查点抑制剂（CPI）疗法在癌症治疗方面取得了进展，但许多癌症仍然具有耐药性。由于缺乏 T 细胞浸润而被视为“冷”的肿瘤显示 CPI 治疗的潜力较低。癌症疫苗可以通过诱导所需的抗肿瘤T细胞反应，与CPI协同作用并克服耐药性，从而克服现有T细胞的不足。将CT26和TC1肿瘤细胞皮下注射到小鼠体内。小鼠接受单独的 CPI 组合治疗或针对 TC1 细胞中存在的肿瘤抗原 E7 特异性的癌症疫苗治疗。选择 TC1 模型的 CPI 是因为对 TC1 肿瘤进行免疫表型分析。探讨了抗肿瘤和促肿瘤免疫、肿瘤大小和存活、疫苗和 CPI 给药的顺序和时间，以及年轻和老年小鼠的治疗效果。而“热”CT26 肿瘤可以单独使用第二代 CPI 或与抗肿瘤药物联合治疗。 -TGFβ，“冷”TC1 肿瘤减少需要肿瘤抗原特异性疫苗与两种 CPI（抗 TIGIT 和抗 PD-L1）的协同作用，这是通过肿瘤微环境 (TME) 表征预测的。协同三重组合比任何成对组合都能更好地延迟肿瘤生长，并以 CD8 T 细胞依赖性方式提高生存率。 CD4 T 细胞的消耗改善了治疗反应，而调节性 T 细胞 (Treg) 的消耗表明 Treg 会抑制反应，正如 TME 分析所预测的那样。我们发现 CPI 和疫苗施用的顺序决定了治疗的成功，并且同时施用的三重组合诱导了最高的 E7 特异性 T 细胞反应。与年轻小鼠相反，在老年小鼠中，单独使用癌症疫苗是无效的，需要 CPI 来延缓肿瘤生长。这些发现表明，预先存在的或疫苗介导的从头 T 细胞反应可以通过协同 CPI 和 CPI 来放大和促进。 Treg 耗竭共同带来更高的生存率，以及 TME 分析如何帮助合理设计联合疗法和精准医学，以增强对 CPI 和癌症疫苗疗法的临床反应。© 作者（或其雇主）2024。 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many cancers remain resistant. Tumors deemed "cold" based on lack of T cell infiltration show reduced potential for CPI therapy. Cancer vaccines may overcome the inadequacy of existing T cells by inducing the needed antitumor T cell response to synergize with CPIs and overcome resistance.CT26 and TC1 tumor cells were injected subcutaneously into mice. Mice were treated with combinations of CPIs alone or a cancer vaccine specific to the tumor antigen E7 present in TC1 cells. CPIs for the TC1 model were selected because of immunophenotyping TC1 tumors. Antitumor and protumor immunity, tumor size and survival, sequence and timing of vaccine and CPI administration, and efficacy of treatment in young and aged mice were probed.While "hot" CT26 tumors are treatable with combinations of second-generation CPIs alone or with anti-TGFβ, "cold" TC1 tumor reduction requires the synergy of a tumor-antigen-specific vaccine in combination with two CPIs, anti-TIGIT and anti-PD-L1, predicted by tumor microenvironment (TME) characterization. The synergistic triple combination delays tumor growth better than any pairwise combination and improves survival in a CD8+T cell-dependent manner. Depletion of CD4+T cells improved the treatment response, and depleting regulatory T cells (Treg) revealed Tregs to be inhibiting the response as also predicted from TME analysis. We found the sequence of CPI and vaccine administration dictates the success of the treatment, and the triple combination administered concurrently induces the highest E7-specific T cell response. Contrary to young mice, in aged mice, the cancer vaccine alone is ineffective, requiring the CPIs to delay tumor growth.These findings show how pre-existing or vaccine-mediated de novo T cell responses can both be amplified by and facilitate synergistic CPIs and Treg depletion that together lead to greater survival, and how analysis of the TME can help rationally design combination therapies and precision medicine to enhance clinical response to CPI and cancer vaccine therapy.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.