LSD1 inhibition corrects dysregulated MHC-I and dendritic cells activation through IFNγ-CXCL9-CXCR3 axis to promote antitumor immunity in HNSCC

Chakraborty, A. K.; Kroehling, L.; Raut, R.; Choudhury, C.; Kukuruzinska, M.; Gutkind, J. S. V.; Varelas, X.; Sahay, B.; Monti, S.; Bais, M. V.

doi:10.1101/2025.03.17.643710

bioRxiv · 10.1101/2025.03.17.643710

LSD1 inhibition corrects dysregulated MHC-I and dendritic cells activation through IFNγ-CXCL9-CXCR3 axis to promote antitumor immunity in HNSCC

Chakraborty, A. K.·Kroehling, L.·Raut, R.·Choudhury, C.·Kukuruzinska, M.·Gutkind, J. S. V.·Varelas, X.·Sahay, B.·Monti, S.·Bais, M. V.

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Abstract

Poor infiltration of CD8+ T cells and dysregulated MHC-I confer resistance to anticancer clinical therapies. This study aimed to elucidate the mechanisms of lysine-specific demethylase 1 (LSD1, encoded by KDM1A gene) in antitumor immunity in Head and Neck Squamous cell carcinoma (HNSCC). LSD1 inhibition in syngeneic and chronic tobacco carcinogen-induced HNSCC mice recruited activated dendritic cells (DCs), CD4+ and CD8+ T cells, enriched interferon-gamma (IFN{gamma}) in T cells, CXCL9 in DCs, and CXCR3 in T cells, as evaluated using flow cytometry and single-cell RNA-seq analysis. Humanized HNSCC mice and TCGA data validated the inverse correlation of KDM1A with DC markers, CD8+ T cells, and their activating chemokines. Kdm1a knockout in mouse HNSCC and LSD1 inhibitor treatment to co-culture of human HNSCC cells with human peripheral blood mononuclear cells (PBMCs) resulted in MHC-I upregulation in cancer cells for efficient antigen presentation in tumors. Overall, LSD1 inhibition in tumor cells upregulates MHC class I and induces DCs to produce CXCL9, which in turn activates CD8+ T cells through the CXCL9-CXCR3 axis to produce IFN{gamma}. Finally, we identified a novel mechanism by which LSD1 inhibition promotes the activation of H3K4me2 and its direct interaction with MHC-I to induce antitumor immunity. This may have implications in poorly immunogenic and immunotherapy-resistant cancers. Statement of SignificanceLSD1-mediated unique mechanisms have impact on epigenetic therapy, MHC-I resistant HNSCC therapies, and poor CD8+ and dendritic cell infilterated tumors.

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Chakraborty, A. K., Kroehling, L., Raut, R., Choudhury, C., Kukuruzinska, M., Gutkind, J. S. V., Varelas, X., Sahay, B., Monti, S., Bais, M. V.. 2025-03-17. LSD1 inhibition corrects dysregulated MHC-I and dendritic cells activation through IFNγ-CXCL9-CXCR3 axis to promote antitumor immunity in HNSCC. https://doi.org/10.1101/2025.03.17.643710

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