Emerging evidence has underscored the significance of antitumor humoral immunity, which is associated with the development of T follicular helper (Tfh) cell. However, the molecular mechanisms underlying Tfh differentiation in antitumor immunity remains poorly understood. We analyzed publicly available RNA-seq data across various representative immune models to identify signature pathways of Tfh cells. Subsequently, we generated T-cell-specific Mek1/2 knockout mice and investigated the functional phenotypes through Tfh cell polarization, adoptive transfer, and flow cytometry assays. Next, we employed multi-omics sequencing and overexpression experiments to delineate the underlying mechanisms of cellular phenotypes. Finally, by integrated analysis of scRNA-seq datasets combined with MEK inhibitor intervention studies, we elucidated the anti-tumor humoral responses of MEK inhibitors in both murine tumor models and TCGA-SKCM patient cohort. Mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling was identified as a potential regulator of Tfh cells and antitumor humoral response. Codeletion or pharmacological inhibition of MEK1/2 effectively promoted Tfh cell development in vitro and in vivo. Mechanistically, ATAC-seq and RNA-seq integrative analysis revealed interferon regulatory factor 4 (IRF4)-dependent epigenetic modulation of characteristic Tfh cell genes, thereby driving Tfh differentiation. Overexpression of Irf4 counteracted Mek1/2 ablation-mediated Tfh cell generation. Moreover, MEK1/2 inhibitor therapy enhanced Tfh infiltration coupled with humoral immune responses in murine melanoma model and was correlated with favorable clinical prognosis in melanoma patients. Our study revealed the MEK1/2-IRF4 axis potentiates Tfh development to enhance the antitumor humoral response. These findings may provide an unprecedented strategy to improve antitumor immunotherapy efficacy by harnessing humoral immune responses.
Ran et al. (Mon,) studied this question.