Antibody targeting tumor-derived soluble NKG2D ligand sMIC reprograms NK cell homeostatic survival and function and enhances melanoma response to PDL1 blockade therapy
Antibody targeting tumor-derived soluble NKG2D ligand sMIC reprograms NK cell homeostatic survival and function and enhances melanoma response to PDL1 blockade therapy
复制标题
DOI：
10.1186/s13045-020-00896-0
复制
发表时间：
2020-06-09
影响因子：
28.5
通讯作者：
Wu, Jennifer D.
中科院分区：
文献类型：
--
作者：
Basher, Fahmin;Dhar, Payal;Wu, Jennifer D.
在基线或PD 1/PDL 1阻断治疗后血清可溶性NKG 2D配体可检测的黑色素瘤患者总体生存率较差。在可溶性人NKG 2D配体家族中，发现可溶性人MHC I链相关分子（sMIC）在黑色素瘤患者中升高，并且主要与对PD 1/PDL 1阻断治疗的不良反应相关。方法在本研究中，我们的目的是研究是否共同靶向肿瘤释放的sMIC增强PD 1/PDL 1阻断治疗黑色素瘤的疗效。我们将表达sMIC的B16 F10黑色素瘤肿瘤植入同基因宿主中，并评估抗sMIC抗体和抗PDL 1抗体联合治疗与单药治疗相比的疗效。我们分析了相关的效应机制。我们还评估了转移性人黑色素瘤中的sMIC/MIC患病率。结果我们发现，与单一疗法相比，抗PDL 1抗体与靶向sMIC的抗体的联合疗法显著改善了动物存活率，并且联合疗法的效果显著依赖于NK细胞。我们表明，联合治疗显著增加了NK细胞上的IL-2 R α（CD 25），这使NK细胞对低剂量IL-2敏感，从而存活。我们证明，sMIC负重编程与NK细胞稳态存活和增殖相关的基因表达，并且清除sMIC的抗体逆转sMIC的作用并重编程NK细胞以存活。我们进一步表明，sMIC/MIC是大量存在于转移性人黑色素瘤肿瘤。结论我们的研究结果提供了一个临床前概念验证和一个新的机制的理解，强调抗体靶向sMIC的意义，以提高抗PD 1/PDL 1抗体的MIC/sMIC（+）转移性黑色素瘤患者的治疗效果。
Background Melanoma patients who have detectable serum soluble NKG2D ligands either at the baseline or post-treatment of PD1/PDL1 blockade exhibit poor overall survival. Among families of soluble human NKG2D ligands, the soluble human MHC I chain-related molecule (sMIC) was found to be elevated in melanoma patients and mostly associated with poor response to PD1/PDL1 blockade therapy. Methods In this study, we aim to investigate whether co-targeting tumor-released sMIC enhances the therapeutic outcome of PD1/PDL1 blockade therapy for melanoma. We implanted sMIC-expressing B16F10 melanoma tumors into syngeneic host and evaluated therapeutic efficacy of anti-sMIC antibody and anti-PDL1 antibody combination therapy in comparison with monotherapy. We analyzed associated effector mechanism. We also assessed sMIC/MIC prevalence in metastatic human melanoma tumors. Results We found that the combination therapy of the anti-PDL1 antibody with an antibody targeting sMIC significantly improved animal survival as compared to monotherapies and that the effect of combination therapy depends significantly on NK cells. We show that combination therapy significantly increased IL-2R alpha (CD25) on NK cells which sensitizes NK cells to low dose IL-2 for survival. We demonstrate that sMIC negatively reprograms gene expression related to NK cell homeostatic survival and proliferation and that antibody clearing sMIC reverses the effect of sMIC and reprograms NK cell for survival. We further show that sMIC/MIC is abundantly present in metastatic human melanoma tumors. Conclusions Our findings provide a pre-clinical proof-of-concept and a new mechanistic understanding to underscore the significance of antibody targeting sMIC to improve therapeutic efficacy of anti-PD1/PDL1 antibody for MIC/sMIC(+)metastatic melanoma patients.