Tumoral and stromal hMENA isoforms influence tertiary lymphoid structure localization and predict response to immunocheckpoint blockade in lung cancer patients

ABSTRACT: The advent of immunotherapy in the clinical practice of non-small cell lung cancer (NSCLC) have highlighted the impact of the tumor immune microenvironment in the control of the tumor progression, as well as in the response to immune checkpoint blockade (ICB) therapy. Tertiary Lymphoid Structures (TLS), determinants of antitumor immunity, are associated with a favorable clinical outcome in NSCLC patients and with the effectiveness of ICB in several tumors. The actin regulatory protein hMENA undergoes tissue-specific splicing, with tumors expressing hMENA11ahigh/ stromal fibronectin (FN1)low related to early N0 NSCLC patients with a favorable prognosis. hMENA/hMENA∆v6 is overexpressed in pro-tumoral CAFs related to the subtype of immunosuppressive ECM-my-CAF Herein, by analyzing the pattern of hMENA isoform expression in tumor cells and CAFs, we highlighted the role of hMENA as a crucial factor in the communication among tumor cells CAFs, T and B cells. Mechanistically, we demonstrated that in NSCLC cell lines hMENA11a increases the expression of the TLS regulator LTβR, reduces the FN1 expression and favors CXCL13 production by tissue resident T cells. Conversely in CAFs, hMENA/hMENAΔv6 inhibits the NF-kB pathway downstream to LTβR and the secretion of CXCL13, crucial in TLS formation. Of clinical relevance, our experimental data support our finding in primary tumors that TLS localized within the tumor area (TLS-IT) are predictive of a longer disease-free survival in N0 NSCLC patients and are accompanied by the maturation of B cells in the tumor tissue. TLS-IT associate with paucity of hMENA positive CAFs, low stromal FN1 and high hMENA11a tumor cell expression. To translate these results in a clinical setting of ICB treated patients, we identified a signature based on the pattern of hMENA isoforms, FN1 and LTβR expression that may discriminate NSCLC patients responding or not-responding to ICB.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217451 | GEO | 2023/08/30

REPOSITORIES: GEO