MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Prasad, M.; Zorea, J.; Jagadeeshan, S.; Shnerb, A.; Bouaoud, J.; Michon, L.; Novoplansky, O.; Badarni, M.; Cohen, L.; Yagodayev, K.; Tzadok, S.; Rotblat, B.; Brezina, L.; Mock, A.; Karabajakian, A.; Fayette, J.; Cohen, I.; Cooks, T.; Allon, I.; Dimitstei, O.; Joshua, B.; Kong, D.; Voronov, E.; Scaltriti, M.; Carmi, Y.; Hess, J.; Morris, L. G. T.; Saintigny, P.; Elkabets, M.

doi:10.1101/2021.08.22.457244

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bioRxiv · 10.1101/2021.08.22.457244

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

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Abstract

Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Using pre-clinical HNC models, we demonstrated that treatment with the MEK1/2 blocker trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the anti-tumor immunity of CD8+ T cells. Further activation of CD8+ T cells by supplementation with anti-programmed death-1 (PD-1) antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to PD-1-supplementation by attenuating the expression of tumor-derived colony-stimulating factor-1 (CSF-1), which reduced the abundance of two CSF-1R+CD11c+ myeloid-derived suppressor cell (MDSC) populations in the tumor microenvironment (TME). In contrast, prolonged treatment with trametinib abolished the anti-tumor activity of PD-1, because tumor cells undergoing the epithelial to mesenchymal transition (EMT) in response to trametinib restored CSF-1 expression and re-created an immune-suppressive TME. These findings provide the rationale for testing the trametinib/PD-1 combination in HNC and highlight the importance of sensitizing tumors to immunotherapies by using targeted therapies to interfere with the host-tumor interaction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/457244v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1c65286org.highwire.dtl.DTLVardef@1541becorg.highwire.dtl.DTLVardef@f557f3org.highwire.dtl.DTLVardef@16134dc_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

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Prasad, M., Zorea, J., Jagadeeshan, S., Shnerb, A., Bouaoud, J., Michon, L., Novoplansky, O., Badarni, M., Cohen, L., Yagodayev, K., Tzadok, S., Rotblat, B., Brezina, L., Mock, A., Karabajakian, A., Fayette, J., Cohen, I., Cooks, T., Allon, I., Dimitstei, O., Joshua, B., Kong, D., Voronov, E., Scaltriti, M., Carmi, Y., Hess, J., Morris, L. G. T., Saintigny, P., Elkabets, M.. 2021-08-22. MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer. https://doi.org/10.1101/2021.08.22.457244

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