Dysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer

EGFR mutant lung tumours do not respond favourably to immunotherapy. Here, using single cell sequencing, the authors find that tissue resident memory CD8(+) T like cells are reduced in the immune landscape of EGFR mutant tumours in comparison to wild type tumours and the presence of these cells may predict response to immunotherapy. 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 (T-FH)-like cells, and tissue-resident memory CD8(+) T (T-RM)-like cells decreased in EGFR-MT tumors. The NOTCH-RBPJ regulatory network, which is vital for persistence of T-RM state, is perturbed, and the interactions between T-FH and B cells through the CXCL13-CXCR5 axis disappear in EGFR-MT tumors. Notably, the proportion of T-RM-like cells is predictive for anti-PD-1 response in NSCLC. Our findings suggest that the impairment of T-FH-B-T-RM cooperation in tertiary lymphoid structure formation, accompanied by the dysregulation of T-RM homeostasis and the loss of T-FH-B crosstalk, underlies unfavorable anti-PD-1 response in EGFR-MT lung tumors.