Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea.
Commun Biol. 2022 Feb 24;5(1):167. doi: 10.1038/s42003-022-03103-7.
KRAS/LKB1 (STK11) NSCLC metastatic tumors are intrinsically resistant to anti-PD-1 or PD-L1 immunotherapy. In this study, we use a humanized mouse model to show that while carboplatin plus pembrolizumab reduce tumor growth moderately and transiently, the addition of the tumor suppressor gene TUSC2, delivered systemically in nanovesicles, to this combination, eradicates tumors in the majority of animals. Immunoprofiling of the tumor microenvironment shows the addition of TUSC2 mediates: (a) significant infiltration of reconstituted human functional cytotoxic T cells, natural killer cells, and dendritic cells; (b) induction of antigen-specific T cell responses; (c) enrichment of functional central and memory effector T cells; and (d) decreased levels of PD-1 T cells, myeloid-derived suppressor cells, Tregs, and M2 tumor associated macrophages. Depletion studies show the presence of functional central and memory effector T cells are required for the efficacy. TUSC2 sensitizes KRAS/LKB1 tumors to carboplatin plus pembrolizumab through modulation of the immune contexture towards a pro-immune tumor microenvironment.
KRAS/LKB1 (STK11) NSCLC 转移性肿瘤对抗 PD-1 或 PD-L1 免疫疗法具有内在抗性。在这项研究中，我们使用人源化小鼠模型表明，虽然卡铂加派姆单抗适度且短暂地减少肿瘤生长，但全身性递送肿瘤抑制基因 TUSC2 的纳米囊泡的添加，可使大多数动物的肿瘤完全消除。肿瘤微环境的免疫分析表明，TUSC2 的添加介导：（a）重建的功能性细胞毒性 T 细胞、自然杀伤细胞和树突状细胞的显著浸润；（b）诱导抗原特异性 T 细胞反应；（c）功能性中央和记忆效应 T 细胞的富集；以及（d）PD-1 T 细胞、髓系来源的抑制细胞、Tregs 和 M2 肿瘤相关巨噬细胞水平降低。耗竭研究表明，功能中央和记忆效应 T 细胞的存在是疗效所必需的。TUSC2 通过调节免疫微环境向有利于免疫的肿瘤微环境，使 KRAS/LKB1 肿瘤对卡铂加派姆单抗敏感。
