PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：尽管检查点抑制剂（CPI）疗法在癌症治疗中取得了进展，许多癌症仍然具有抵抗力。基于缺乏T细胞浸润而被视为“冷”的肿瘤显示出降低的CPI治疗潜力。癌症疫苗可以通过诱导所需的抗肿瘤T细胞应答以与CPIs协同并克服抗性来克服现有T细胞的不足。
方法:将CT26和TC1肿瘤细胞皮下注射到小鼠体内。用单独的CPIs或对TC1细胞中存在的肿瘤抗原E7具有特异性的癌症疫苗的组合处理小鼠。选择TC1模型的CPIs是因为TC1肿瘤的免疫表型。抗肿瘤和质子免疫，肿瘤大小和存活率，疫苗和CPI给药的顺序和时间，并对年轻和老年小鼠的治疗效果进行了探讨。
结果：虽然“热”CT26肿瘤可以单独使用第二代CPIs或与抗TGFβ联合治疗，“冷”TC1肿瘤减少需要肿瘤抗原特异性疫苗与两种CPIs的协同作用，通过肿瘤微环境（TME）表征预测的抗TIGIT和抗PD-L1。协同三重组合比任何成对组合更好地延迟肿瘤生长并且以CD8+T细胞依赖性方式改善存活。CD4+T细胞的耗尽改善了治疗反应，和耗尽调节性T细胞(Treg)揭示Treg抑制应答,如从TME分析预测的。我们发现CPI和疫苗给药的顺序决定了治疗的成功，和同时施用的三联组合诱导最高的E7特异性T细胞应答。与年轻老鼠相反，在老年小鼠中，癌症疫苗本身是无效的，需要CPIs来延缓肿瘤生长。
结论：这些研究结果表明，预先存在的或疫苗介导的从头T细胞反应可以被CPIs和Treg协同消耗放大，并促进它们共同导致更大的存活率。以及对TME的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。
方法:将CT26和TC1肿瘤细胞皮下注射到小鼠体内。用单独的CPIs或对TC1细胞中存在的肿瘤抗原E7具有特异性的癌症疫苗的组合处理小鼠。选择TC1模型的CPIs是因为TC1肿瘤的免疫表型。抗肿瘤和质子免疫，肿瘤大小和存活率，疫苗和CPI给药的顺序和时间，并对年轻和老年小鼠的治疗效果进行了探讨。
结果：虽然“热”CT26肿瘤可以单独使用第二代CPIs或与抗TGFβ联合治疗，“冷”TC1肿瘤减少需要肿瘤抗原特异性疫苗与两种CPIs的协同作用，通过肿瘤微环境（TME）表征预测的抗TIGIT和抗PD-L1。协同三重组合比任何成对组合更好地延迟肿瘤生长并且以CD8+T细胞依赖性方式改善存活。CD4+T细胞的耗尽改善了治疗反应，和耗尽调节性T细胞(Treg)揭示Treg抑制应答,如从TME分析预测的。我们发现CPI和疫苗给药的顺序决定了治疗的成功，和同时施用的三联组合诱导最高的E7特异性T细胞应答。与年轻老鼠相反，在老年小鼠中，癌症疫苗本身是无效的，需要CPIs来延缓肿瘤生长。
结论：这些研究结果表明，预先存在的或疫苗介导的从头T细胞反应可以被CPIs和Treg协同消耗放大，并促进它们共同导致更大的存活率。以及对TME的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。
