Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer.
Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer.
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DOI：
10.1158/2326-6066.cir-13-0058
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发表时间：
2013-08
影响因子：
10.1
通讯作者：
Schreiber H
中科院分区：
文献类型：
--
作者：
Binder DC;Engels B;Arina A;Yu P;Slauch JM;Fu YX;Karrison T;Burnette B;Idel C;Zhao M;Hoffman RM;Munn DH;Rowley DA;Schreiber H
即使 CD8+ T 细胞大量浸润，免疫原性肿瘤也会逐渐生长。我们研究了如何挽救长期存在的免疫原性黑色素瘤中的 CD8+ T 细胞功能，这些黑色素瘤含有高比例的功能失调的内源性 PD-1+ 肿瘤特异性 CD8+ T 细胞。使用 αPD-L1 和 αCTLA-4 阻断抗体治疗并不能阻止肿瘤快速进展。然后，我们使用鼠伤寒沙门氏菌 A1-R 测试了将外源肿瘤特异性抗原递送到肿瘤中，以增加抗原水平并产生促炎性肿瘤微环境。产生抗原的 A1-R 挽救了内源性肿瘤特异性 CD8+ T 细胞反应：在淋巴器官中诱导增殖，并且在肿瘤中恢复效应器功能。使用产生抗原的 A1-R 治疗可提高小鼠的存活率，并使长期存在的免疫原性黑色素瘤的排斥率达到 32%。在用产生抗原的 A1-R 治疗后，大多数肿瘤特异性 CD8+ T 细胞在肿瘤中仍然表达高水平的 PD-1。将产生抗原的 A1-R 与 αPD-L1 阻断抗体相结合，增强了肿瘤特异性 CD8+ T 细胞的扩增，并导致 80% 的肿瘤排斥。总的来说，这些数据证明了一种强大的新治疗方法可以挽救功能失调的内源性肿瘤特异性 CD8+ T 细胞并根除晚期免疫原性肿瘤。
Immunogenic tumors grow progressively even when heavily infiltrated by CD8+ T cells. We investigated how to rescue CD8+ T cell function in long-established immunogenic melanomas that contained a high percentage of endogenous PD-1+ tumor-specific CD8+ T cells that were dysfunctional. Treatment with αPD-L1 and αCTLA-4 blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8+ T cell response: proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8+ T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1 blocking antibody enhanced the expansion of tumor-specific CD8+ T cells and resulted in 80% tumor rejection. Collectively, these data demonstrate a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8+ T cells and eradicate advanced immunogenic tumors.