한빛사 논문
Jae-Won Cho1, Seyeon Park2, Gamin Kim3, Heonjong Han1, Hyo Sup Shim4, Sunhye Shin3, Yong-Soo Bae5, Seong Yong Park6,*, Sang-Jun Ha2,*, Insuk Lee1,* & Hye Ryun Kim3,*
1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea. 2Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea. 3Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea. 4Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea. 5Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, Korea. 6Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.
*Corresponding author.
Abstract
Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations exhibit an unfavorable response to PD-1 inhibitor through unclear mechanisms. Hypothesizing that EGFR mutations alter tumor-immune interactions, we compare tumor-infiltrating lymphocytes between EGFR mutant (EGFR-MT) and wild type (EGFR-WT) tumors through single-cell transcriptomic analysis. We find that B cells, CXCL13-producing follicular helper CD4+ T (TFH)-like cells, and tissue-resident memory CD8+ T (TRM)-like cells decreased in EGFR-MT tumors. The NOTCH-RBPJ regulatory network, which is vital for persistence of TRM state, is perturbed, and the interactions between TFH and B cells through the CXCL13-CXCR5 axis disappear in EGFR-MT tumors. Notably, the proportion of TRM-like cells is predictive for anti-PD-1 response in NSCLC. Our findings suggest that the impairment of TFH-B-TRM cooperation in tertiary lymphoid structure formation, accompanied by the dysregulation of TRM homeostasis and the loss of TFH-B crosstalk, underlies unfavorable anti-PD-1 response in EGFR-MT lung tumors.
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