Huang Ruichen, Zhou Qiao, Liu Jiajun, Xia Yang, Jiao Yang, Zhao Bi, Feng Tangtao, Zhou Haosu, Song Xiuyan, Qin Hao, Wang Jun, Cheng Lan, Ning Yunye, Sun Qinying, Liu Yanfang, Su Xiaoping, Dong Yuchao, Zhang Wei
Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Second Military Medical University, Shanghai, 200433, PR China.
Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Second Military Medical University, Shanghai, 200433, PR China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.
Neoplasia. 2025 Jan;59:101088. doi: 10.1016/j.neo.2024.101088. Epub 2024 Nov 22.
The neoantigen vaccine has remarkable potential in treating advanced cancer due to its tumor specificity and ability to bypass central tolerance mechanisms. However, numerous neoantigens show poor immunogenicity, and the immune inhibitory factors of present in both tumors and tumor-draining lymph nodes impair the efficacy of cancer neoantigen vaccine. Eliminating immunosuppressive cells will improve the priming and expansion of anti-tumor immune cells induced by the vaccine.
In this study, a Treg-depleting regimen (consisting of CD25mAb and low-dose cyclophosphamide (LD-CTX)) was used in conjunction with a neoantigen vaccine for treating mice with solid tumors. We constructed two types of tumor models and investigated differences in therapy efficacy in the four groups (PBS, vaccine, CD25mAb+CTX and combination) at the genetic and protein levels. ELISPOT and TCR sequencing were applied to detect the expansion of neoantigen reactive T cells (NRT) and tumor antigen spreading.
In the combinational group, the ELISPOT results showed an obvious expansion of NRT cells induced by weak immunogenic peptides. The combinational group exhibited significant improvement in inhibiting the tumor growth extended the survival time of tumor-bearing mice, and promoted T cells infiltration into tumors. Besides, compared to the Vac group, more neoantigen-targeted and TAA-targeted T cells were detected in the combinational group by TCR sequencing. The results of transcriptomic sequencing and flow cytometry showed that the number of Tregs in the combinational group was lower, while the proportions of memory effector T cells and effector T cells were higher than those in the vaccine group. An increase in mature DCs was also observed in vaccinated mice after receiving this Treg-depleting strategy.
Our research first revealed that inhibiting the normal function of Tregs transformed "weaker" neoantigens into "stronger" ones, while also contributing to the proliferation of NRT cells. This Treg-depleting strategy allowed neoantigens with poor immunogenicity to elicit a robust immune response, thereby augmenting the efficacy of the neoantigen vaccine in delaying tumor growth and prolonging the survival of the hosts.
新抗原疫苗因其肿瘤特异性和绕过中枢耐受机制的能力，在治疗晚期癌症方面具有显著潜力。然而，众多新抗原的免疫原性较差，肿瘤及肿瘤引流淋巴结中存在的免疫抑制因子会损害癌症新抗原疫苗的疗效。清除免疫抑制细胞将改善疫苗诱导的抗肿瘤免疫细胞的启动和扩增。
在本研究中，一种去除调节性T细胞的方案（由CD25单克隆抗体和低剂量环磷酰胺（LD-CTX）组成）与新抗原疫苗联合用于治疗实体瘤小鼠。我们构建了两种肿瘤模型，并在基因和蛋白质水平上研究了四组（PBS、疫苗、CD25单克隆抗体+环磷酰胺和联合组）的治疗效果差异。应用酶联免疫斑点法（ELISPOT）和T细胞受体测序来检测新抗原反应性T细胞（NRT）的扩增和肿瘤抗原扩散。
在联合组中，ELISPOT结果显示弱免疫原性肽诱导的NRT细胞明显扩增。联合组在抑制肿瘤生长方面有显著改善，延长了荷瘤小鼠的生存时间，并促进了T细胞浸润到肿瘤中。此外，与疫苗组相比，联合组通过TCR测序检测到更多针对新抗原和肿瘤相关抗原的T细胞。转录组测序和流式细胞术结果显示，联合组中调节性T细胞的数量较低，而记忆效应T细胞和效应T细胞的比例高于疫苗组。在接受这种去除调节性T细胞的策略后，接种疫苗的小鼠中成熟树突状细胞也有所增加。
我们的研究首次揭示，抑制调节性T细胞的正常功能可将“较弱”的新抗原转化为“较强”的新抗原，同时也有助于NRT细胞的增殖。这种去除调节性T细胞的策略使免疫原性较差的新抗原引发强大的免疫反应，从而增强新抗原疫苗在延缓肿瘤生长和延长宿主生存方面的疗效。
