Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival
Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival
复制标题
DOI：
10.1172/jci.insight.96836
复制
发表时间：
2018-07-12
期刊：
影响因子：
8
通讯作者：
Mittal, Vivek
中科院分区：
文献类型：
--
作者：
Markowitz, Geoffrey J.;Havel, Lauren S.;Mittal, Vivek
免疫检查点抑制剂在晚期非小细胞肺癌（NSCLC）中的成功，促进了它们在早期疾病新辅助治疗中的应用。然而，早期免疫反应的细胞和分子机制对治疗仍然知之甚少。通过对早期NSCLC患者和Kras突变小鼠模型的综合分析，我们发现普遍存在程序性细胞死亡1/程序性细胞死亡1配体1（PD-1/PD-L1）轴，以肿瘤内PD-1(+) T细胞和PD-L1表达增加为例。值得注意的是，肿瘤的进展与免疫微环境的时空调节有关，在肿瘤生长的后期，免疫抑制表型占主导地位。重要的是，PD-1抑制控制了肿瘤生长，提高了总体存活率，并重新编程了肿瘤相关的淋巴细胞和骨髓细胞。T淋巴细胞亚群的耗竭证明了这些群体对PD-1抑制肿瘤生长的协同作用。转录组分析显示T细胞亚群特异性改变对应于对治疗的反应程度。这些结果为PD-1/PD-L1激活和抑制的表型效应的时间进化提供了见解，并激发了肺癌进展早期该轴的靶向性。
Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1(+) T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment with dominant immunosuppressive phenotypes at later phases of tumor growth. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition and motivate targeting of this axis early in lung cancer progression.