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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.

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 (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.

SUBMITTER: Cho JW

PROVIDER: S-EPMC8523541 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeReactive oxygen species modulator 1 (Romo1) is a novel protein that regulates the production of intracellular reactive oxygen species. Romo1 has been shown to be associated with poor survival in various clinical settings for the treatment of lung cancer. In this study, we evaluated whether tissue Romo1 expression was associated with clinical outcomes in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma treated with tyrosine kinase inhibitors (TKIs).MethodRomo1 expression in tumor tissues was examined by immunohistochemistry and evaluated by histologic score. Univariate and multivariate analyses were performed to identify the clinicopathologic parameters, including Romo1 expression, which may be associated with progression-free survival (PFS), overall survival (OS), and incidence of secondary T790M mutation.ResultsA total of 96 tumor specimens were analyzed. With the cut-off value of 200, 71 (74.0%) and 25 (26.0%) patients were classified into low and high Romo1 groups, respectively. The median PFS of the high Romo1 group was significantly shorter than that of the low Romo1 group (13.1 vs 19.9 months, p = 0.0165). The median OS of the high Romo1 group was also significantly shorter than that of the low Romo1 group (19.8 vs 37.0 months, p = 0.0006). Multivariate analyses showed that high Romo1 expression was independently associated with both poor PFS (hazard ratio [HR] = 2.48, 95% confidence interval [CI]: 1.35-4.56, p = 0.0034) and poor OS (HR = 3.17, 95% CI: 1.57-6.41, p = 0.0013). In addition, the rate of secondary T790M mutation after TKI failure was significantly lower in the high Romo1 group than the low Romo1 group (16.7% vs. 38.3%, p = 0.0369).ConclusionsRomo1 overexpression was associated with poor response to treatment and short survival in patients treated with EGFR-TKIs, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach. In addition, our data highlight that Romo1 could be a potential predictive and prognostic biomarker for this patient population.

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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.

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

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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.