Abstract 6102: Single-cell RNA sequencing of lung adenocarcinoma patients reveals age-dependent tumour microenvironment alterations that facilitate response to immunotherapy

Background: Immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD). While the increase in cancer incidence with age and age-associated changes in immune function have been well characterized, age-related differences in the intratumoral immune populations and how this affects immunotherapy response remain unknown. Methods: We collected clinical data from 3,544 samples treated with immune checkpoint blockade (ICB) at the pan-cancer level. Single-cell RNA sequencing data from 19 LUAD samples were integrated and analyzed. Cell types were identified based on canonical marker gene expression. Results: Aged individuals responded more efficiently to ICB treatment at the pan-cancer level. By focusing on LUAD, we showed that patients aged above 46 responded better and had longer progression-free survival than younger counterparts. Further, we presented a 58,031-cell catalog of age-associated single-cell transcriptomes from LUAD patients. Our analysis revealed the accumulation of immune response and chronic inflammation with increasing age. Aged tissues (> 60 years) displayed dominant exhausted natural killer (NK)/T cells and T regulatory cells and were enriched with two subtypes of tumour-associated macrophages marked by SPP1 and CX3CR1 expression, respectively. Furthermore, the ageing dynamics of stroma cells created a pro-tumor microenvironment reflected by increased angiogenesis and collagen formation. Conclusions: These results revealed an increasing immune-suppressive tumour microenvironment with age, supporting an observation of improved ICB response in older LUAD patients. Our extensive single-cell analysis enhances the understanding of age-dependent molecular and cellular dynamics in LUAD. Our results highlight the importance of considering age as a factor for ICB response and provide a rich resource for developing therapeutic targets in LUAD-microenvironment interactions. Citation Format: Xiaoqiang Zhu, Hai Wang, Xuefeng Pan, Jie Hong, Jason Wing Hon Wong, Haoyan Chen, Youwei Zhang. Single-cell RNA sequencing of lung adenocarcinoma patients reveals age-dependent tumour microenvironment alterations that facilitate response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6102.