Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and.
Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
Clin Cancer Res. 2014 Jul 1;20(13):3485-95. doi: 10.1158/1078-0432.CCR-13-2522. Epub 2014 May 5.
The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anticancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test whether Toll-like receptor (TLR) agonists and anticancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic.
We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anticancer agent 1-β-D-arabinofuranosylcytosine (Ara-C). The effects on the immunogenicity of tumor cells were measured in transfer experiments and in vitro studies.
The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anticancer effects of the genotoxic agent Ara-C. Mice injected with cotreated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells. Cotreatment had no effect on the rate of apoptosis or proliferation of Ara-C-treated cells, but upregulated the expression of several immunomodulatory molecules. Consistent with an increased immunogenicity of Pam3CSK4 and Ara-C-treated B-cell lymphoma cells, rejection of cotreated tumor cells required natural killer cells and T cells. We demonstrate that the upregulation of immunomodulatory molecules in response to Pam3CSK4 and Ara-C depended in part on NF-κB.
TLR agonists can increase the efficacy of conventional cancer therapies by altering the immunogenicity of B-cell lymphoma cells.
许多癌细胞的低免疫原性以及各种癌症和抗癌疗法的免疫抑制作用一直是开发有效免疫疗法的障碍。我们的目标是测试 Toll 样受体 (TLR) 激动剂和抗癌化疗药物是否协同作用使肿瘤细胞更具免疫原性。
我们用 TLR1/2 激动剂 Pam3CSK4 和致瘤性抗癌药 1-β-D-阿拉伯呋喃糖基胞嘧啶 (Ara-C) 处理 B 细胞淋巴瘤细胞。在转移实验和体外研究中测量了这些处理对肿瘤细胞免疫原性的影响。
TLR1/2 激动剂 Pam3CSK4 处理 B 细胞淋巴瘤细胞增强了致瘤性药物 Ara-C 的抗癌作用。接受共处理肿瘤细胞注射的小鼠比接受 Pam3CSK4 或 Ara-C 处理细胞挑战的小鼠存活时间更长。Pam3CSK4 或 Ara-C 的给药降低了注射肿瘤细胞的小鼠的肿瘤负荷。共处理对 Ara-C 处理细胞的凋亡或增殖率没有影响，但上调了几种免疫调节分子的表达。与 Pam3CSK4 和 Ara-C 处理的 B 细胞淋巴瘤细胞的免疫原性增加一致，共处理肿瘤细胞的排斥需要自然杀伤细胞和 T 细胞。我们证明，Pam3CSK4 和 Ara-C 反应中免疫调节分子的上调部分依赖于 NF-κB。
TLR 激动剂可以通过改变 B 细胞淋巴瘤细胞的免疫原性来提高常规癌症疗法的疗效。
