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Dysregulation of T FH-B-T RM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer

 Jae-Won Cho  ;  Seyeon Park  ;  Gamin Kim  ;  Heonjong Han  ;  Hyo Sup Shim  ;  Sunhye Shin  ;  Yong-Soo Bae  ;  Seong Yong Park  ;  Sang-Jun Ha  ;  Insuk Lee  ;  Hye Ryun Kim 
 NATURE COMMUNICATIONS, Vol.12(1) : 6068, 2021-10 
Journal Title
Issue Date
B-Lymphocytes ; Carcinoma, Non-Small-Cell Lung / genetics ; Carcinoma, Non-Small-Cell Lung / metabolism ; Chemokine CXCL13 / metabolism ; ErbB Receptors / genetics* ; ErbB Receptors / metabolism* ; Female ; Homeostasis ; Humans ; Lung Neoplasms / genetics* ; Lung Neoplasms / metabolism* ; Lung Neoplasms / pathology ; Lymphocyte Cooperation / physiology* ; Lymphocytes, Tumor-Infiltrating ; Male ; Mutation ; Receptors, CXCR5 / metabolism
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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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Park, Seong Yong(박성용) ORCID logo https://orcid.org/0000-0002-5180-3853
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
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