The connection of innate and adaptive anti-cancer immunity

-卡介苗(BCG)是治疗原位癌和非肌肉浸润性、非转移性人尿路上皮癌的标准药物。尽管对这种免疫疗法的反应被认为与(A)大量的体细胞突变和(B)大量的肿瘤浸润性淋巴细胞有关，但最近关于抑制性免疫受体及其配体在肿瘤逃逸中所起作用的研究结果可能为深入了解卡介苗的有效性提供洞察，并为基于免疫的治疗提供新的靶点。本研究采用侵袭性生物发光原位膀胱癌模型--转导荧光素酶(MB49(Luc))的MB49肿瘤细胞，研究PD-L1抗体Avelumab的抗肿瘤作用。MB49(Luc)小鼠肿瘤细胞在膀胱粘膜壁上形成多灶性肿瘤，使人联想到非肌肉浸润性、非转移性尿路上皮癌。MB49(Luc)膀胱癌PD-L1表达呈强阳性，阿维卢单抗具有显著的抗肿瘤作用(P<0.05)。这些抗肿瘤作用更多地依赖于CD4的存在，而不是CD8T细胞，这是由体内免疫细胞耗尽决定的。研究结果表明，在这个膀胱肿瘤模型中，免疫抑制的PD-1/PD-L1复合体的中断释放了局部适应性免疫反应，进而减少了肿瘤的生长。该膀胱肿瘤模型可用于进一步确定宿主抗肿瘤免疫机制，评价原位癌和非肌肉浸润性、非转移性尿路上皮癌的免疫治疗组合，为后续的临床研究提供理论基础。-IL-12的靶向传递可能会将这种细胞因子变成一种更安全、更有效的癌症治疗方法。我们描述了一种新的免疫细胞因子，NHS-IL12，由两个IL-12分子与肿瘤坏死靶向的人IgG1(NHS76)融合而成。人IgG1部分的加入导致NHS-IL12的血浆半衰期比重组IL-12更长，并且在体内对小鼠肿瘤具有选择性靶向性。使用人外周血单个核细胞(PBMCs)进行的体外测试和灵长类动物体内研究的数据都表明，免疫细胞因子治疗后免疫细胞产生的干扰素-γ减少，这表明与单独使用重组IL-12相比，毒性情况有所改善。在三种小鼠肿瘤模型中，NHS-IL12的抗肿瘤效果优于重组IL-12。利用免疫细胞亚群耗竭抗体、流式细胞术、体外细胞毒性和ELISA法进行的机制研究都表明，NHS-IL12的抗肿瘤作用主要是CD8+T细胞依赖的，可能是由IL-12介导的。NHS-IL12治疗与癌症疫苗、放射治疗或化疗相结合，比单独单独治疗产生更大的抗肿瘤效果。这些临床前的发现为这种免疫细胞因子的临床测试提供了理论基础，无论是作为单一药物还是与疫苗、放射和化疗联合使用。

--- Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, non-metastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (a) a high number of somatic mutations and (b) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, non-metastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, non-metastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. --- Targeted delivery of IL-12 might turn this cytokine into a safer, more effective cancer therapeutic. We describe a novel immunocytokine, NHS-IL12, consisting of two molecules of IL-12 fused to a tumor necrosis-targeting human IgG1 (NHS76). The addition of the human IgG1 moiety resulted in a longer plasma half-life of NHS-IL12 than recombinant IL-12, and a selective targeting to murine tumors in vivo. Data from both in vitro assays using human peripheral blood mononuclear cells (PBMCs) and in vivo primate studies showed that IFN-gamma production by immune cells is attenuated following treatment with the immunocytokine, suggesting an improved toxicity profile than seen with recombinant IL-12 alone. NHS-IL12 was superior to recombinant IL-12 when evaluated as an anti-tumor agent in three murine tumor models. Mechanistic studies utilizing immune cell subset-depleting antibodies, flow cytometric methods, and in vitro cytotoxicity and ELISA assays all indicated that the anti-tumor effects of NHS-IL12 were primarily CD8+ T cell-dependent and likely IL-12-mediated. Combining NHS-IL12 treatment with a cancer vaccine, radiation, or chemotherapy resulted in greater anti-tumor effects than each individual therapy alone. These preclinical findings provide a rationale for the clinical testing of this immunocytokine, both as a single agent and in combination with vaccines, radiation and chemotherapy.