The connection of innate and adaptive anti-cancer immunity

关于天然免疫和获得性抗癌免疫之间关系的研究包括：免疫细胞因子NHS-IL12作为一种潜在的癌症治疗：通过将人IL-12异源二聚体与NHS76抗体重链的C末端进行基因融合，设计出一种肿瘤靶向的IL-12免疫细胞因子NHS-IL12。NHS76是一种全人抗体，因其能与DNA/组蛋白结合从而靶向体内肿瘤而被选中。这种抗体的一种放射性标记嵌合形式已被证明可以选择性地靶向人类肿瘤，并已被批准用于中国的肺癌治疗。为了观察NHS-muIL12在小鼠模型中的亚细胞定位，我们给荷瘤小鼠皮下注射(S.C.)用NHS-IL12和清晰的肿瘤靶向性观察到肿瘤细胞核内有明显的染色。在三种不同的肿瘤模型(LLC、MC38和B16)的抗肿瘤研究中，这种免疫细胞因子的表现优于等摩尔剂量的重组小鼠IL-12(rMuIL-12)。结果表明，NHS-muIL12可上调血清中的干扰素-γ水平，上调DC表面MHC-I类蛋白的表达，诱导CD49b+自然杀伤(NK)细胞和CD8+T细胞的增殖，并呈剂量依赖关系。免疫细胞亚群耗竭研究证实，NHS-muIL12的抗肿瘤作用涉及CD8+细胞和NK细胞，这与IL-12的已知作用机制一致。治愈MC38肿瘤的小鼠表现出对肿瘤再攻击的抵抗力，并显示出持久的TAA特异性CTL记忆。与rMuIL-12相比，NHS-muIL-12的疗效增强可能源于免疫细胞因子更有利的药代动力学特性及其与肿瘤的结合能力。NHS-IL12也已用于临床前与几种标准护理疗法的结合。与单独使用任何一种药物相比，当NHS-IL12与(A)分割放射(Lewis肺癌)、(B)TKI sunitinib(Renca肾癌)和(C)多西紫杉醇(MC38结肠癌模型)联合使用时，我们显示出统计上增强的抗肿瘤效果。NHS-IL12的第一阶段研究正在进行中。小剂量的沙拉卡替尼对CD8+T细胞的免疫增强作用，与疫苗联合使用时，可能会对病原体或癌症提供更好的保护。抑制转化生长因子-β1信号转导促进中枢记忆T细胞分化：本研究证实分离的CD8+T细胞在同源多肽识别后表达mRNA并产生转化生长因子-β。通过阻断内源性的转化生长因子-β抗体或抑制转化生长因子-β的小分子抑制剂，可促进CD62LHigh/CD44高中央记忆性CD8+T细胞的产生，并伴随着强烈的回忆反应。有趣的是，中央记忆T细胞池内的增强取代了细胞的增殖或激活，但伴随着常胚层/T-bet转录因子比率的预期增加。然而，信号转导途径(S)似乎是非规范的，独立于SMAD或雷帕霉素信号的哺乳动物靶点。在人类外周血单核细胞中，也证实了通过阻断转化生长因子-β来增强中央记忆的产生。这些发现强调了自分泌转化生长因子-β在T细胞动态平衡中的作用(S)，特别是在效应/记忆和中央/记忆T细胞之间的平衡。这些结果可能为靶向转化生长因子-β信号以增强抗原特异性CD8+T细胞记忆对抗致死性感染或癌症提供了理论基础。

Studies on the connection of innate and adaptive anti-cancer immunity include: The immunocytokine NHS-IL12 as a potential cancer therapeutic: A tumor-targeting interleuken (IL)-12 immunocytokine, NHS-IL12, was engineered by genetically fusing the human IL-12 heterodimers to the C-termini of the heavy chains of the NHS76 antibody. NHS76 is a fully human antibody selected for its specific ability to bind to DNA/histones and thereby target to tumors in vivo. A radiolabeled chimeric form of this antibody has been shown to selectively target human tumors and has been approved for the therapy of lung carcinoma in China. To visualize the subcellular localization of NHS-muIL12 in a murine model, we injected tumor-bearing mice subcutaneously (s.c.) with NHS-IL12 and distinct tumor targeting and staining in the nuclei of tumor cells was observed. This immunocytokine outperformed an equimolar dose of recombinant murine IL-12 (rMuIL-12) in anti-tumor studies of three distinct tumor models (LLC, MC38 and B16). NHS-muIL12 was found to increase serum IFN-gamma levels, upregulate MHC class I protein expression on DCs, and induce the proliferation of CD49b+ natural killer (NK) cells and CD8+ T cells, all in a dose-dependent manner. An immune cell subset depletion study confirmed that the antitumor effects of NHS-muIL12 involves CD8+ cells and NK cells, consistent with the known mechanisms of action of IL-12. Mice that were cured of their MC38 tumors showed resistance to tumor rechallenge and displayed long-lasting TAA-specific CTL memory. This enhanced efficacy observed of NHS-muIL12 vs. rMuIL-12 likely stems from the more favorable pharmacokinetic properties of the immunocytokine and its tumor-binding ability. NHS-IL12 has also been employed preclinically in combination with several standard-of-care therapies. We have shown statistically enhanced anti-tumor effects, compared to the use of either agent alone, when NHS-IL12 was used in combination with (a) fractionated radiation (Lewis lung carcinoma), (b) the TKI sunitinib (Renca renal carcinoma), and (c) docetaxel (MC38 colon cancer model). A Phase I study of NHS-IL12 is ongoing. The immune-potentiating effects on CD8+ T cells by a low dose of saracatinib might afford better protection from pathogens or cancer when combined with vaccine. Inhibition of TGF-beta1 signaling promotes central memory T-cell differentiation: This study affirmed that isolated CD8+ T cells express mRNA and produce TGF-beta following cognate peptide recognition. Blockage of endogenous TGF-beta with either a TGF-beta blocking Ab or a small molecule inhibitor of TGF-betaRI enhances the generation of CD62Lhigh/CD44high central memory CD8+ T cells accompanied with a robust recall response. Interestingly, the augmentation within the central memory T-cell pool occurs in lieu of cellular proliferation or activation, but with the expected increase in the ratio of the Eomesoderm/T-bet transcriptional factors. Yet, the signal transduction pathway(s) seems to be noncanonical, independent of SMAD or mammalian target of rapamycin signaling. Enhancement of central memory generation by TGF-beta blockade is also confirmed in human peripheral blood mononuclear cells. The findings underscore the role(s) that autocrine TGF-beta plays in T-cell homeostasis and, in particular, the balance of effector/memory and central/memory T cells. These results may provide a rationale to targeting TGF-beta signaling to enhance antigen-specific CD8+ T-cell memory against a lethal infection or cancer.