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.
|Publication status||Published - 2021 Dec 1|
Bibliographical noteFunding 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.
© 2021, The Author(s).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)