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, Hye Ryun Kim

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13 Citations (Scopus)


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.

Original languageEnglish
Article number6068
JournalNature communications
Issue number1
Publication statusPublished - 2021 Dec 1

Bibliographical note

Funding Information:
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science and ICT (NRF-2019M3A9B6065231, 2017M3A9E802971, 2017M3A9E9072669 to H.R.K., 2018R1A5A2025079, 2018M3C9A5064709, 2019M3A9B6065192 to I.L., 2019M3A9B6065221, 2018R1A2A1A05076997, 2017R1A5A1014560 to S.-J.H.). The work was supported in part by Brain Korea 21(BK21) FOUR program.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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