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Tertiary Lymphoid Structure and CD8 T Cell Exclusion in Minimally Invasive Adenocarcinoma

By Jin Wang, Dongbo Jiang, Xiaoqi Zheng, Wang Li, Tian Zhao, Di Wang, Huansha Yu, Dongqing Sun, Ziyi Li, Jian Zhang, Zhe Zhang, Likun Hou, Gening Jiang, Fan Zhang, Kun Yang, Peng Zhang

Posted 04 Aug 2020
medRxiv DOI: 10.1101/2020.08.03.20166991

Lung adenocarcinoma is the leading cause of cancer death. To characterize the tumor microenvironment (TME) of early-stage lung adenocarcinoma, we performed RNA-seq profiling on 59 pairs of minimally invasive adenocarcinoma (MIA) tumors and matched adjacent normal lung tissues from Chinese patients. We observed mucin over-expression and glycosylation, and altered cytokine-cytokine interactions in MIA tumors, which also had distinct adaptive immune TME of higher CD4+ T cell infiltration, higher plasma B cell activation, and lower CD8+ T cell infiltration. The high expression of markers for B cells, activated CD4 T cells, and follicular helper T (Tfh) cells in MIA implicated the formation of tertiary lymphoid structures (TLS), which were supported by two independent single-cell RNA-seq data. Multiplex immunohistochemistry (mIHC) staining of 22 MIA tumors validated TLS formation and revealed an enrichment of follicular regulatory T cells (Tfr) in TLS follicles, which may explain the lower CD8+ T cell infiltration and attenuated anti-tumor immunity in MIA.

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