Dysregulation of TFH-B-TRM 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 () and Hye Ryun Kim ()
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Jae-Won Cho: Yonsei University
Seyeon Park: Yonsei University
Gamin Kim: Yonsei University College of Medicine
Heonjong Han: Yonsei University
Hyo Sup Shim: Yonsei University College of Medicine
Sunhye Shin: Yonsei University College of Medicine
Yong-Soo Bae: Sungkyunkwan University
Seong Yong Park: Yonsei University College of Medicine
Sang-Jun Ha: Yonsei University
Insuk Lee: Yonsei University
Hye Ryun Kim: Yonsei University College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26362-0

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