MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression

Hofstatter Azambuja, J.; Yerneni, S. S.; Maurer, L. M.; Crentsil, H. E.; Debom, G. N.; Klei, L.; Smyers, M.; Sneiderman, C. T.; Schwab, K. E.; Acharya, R.; Lin Wu, Y.; Ekambaram, P.; Hu, D.; Gough, P. J.; Bertin, J.; Melnick, A.; Kohanbash, G.; Bao, R.; Lucas, P. C.; McAllister-Lucas, L. M.

doi:10.1101/2024.09.26.614808

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bioRxiv · 10.1101/2024.09.26.614808

MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression

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Abstract

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. Here, we show that MALT1 plays a key role in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-{kappa}B signaling axis within macrophages, leading to macrophage migration and polarization toward an immunosuppressive phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage "M1-like" phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in increased immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. Further, the addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, which may enhance the efficacy of this standard-of-care chemotherapeutic. Together, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/614808v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@18c969eorg.highwire.dtl.DTLVardef@f48f0dorg.highwire.dtl.DTLVardef@1dbbbb1org.highwire.dtl.DTLVardef@ff8237_HPS_FORMAT_FIGEXP M_FIG The effects of tumor cell-induced CARD9-BCL10-MALT1 (CBM) activation (left) and MALT1 protease inhibition (right) on GBM associated macrophages in the tumor microenvironment. Cartoon of cellular components of a GBM tumor with an immunosuppressive TME characterized by "M2-like macrophages" (left) and conversion to a more immune-reactive tumor microenvironment characterized by "M1-like macrophages and increased effector T-cells (right) as a result of MALT1 protease inhibition. C_FIG

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Hofstatter Azambuja, J., Yerneni, S. S., Maurer, L. M., Crentsil, H. E., Debom, G. N., Klei, L., Smyers, M., Sneiderman, C. T., Schwab, K. E., Acharya, R., Lin Wu, Y., Ekambaram, P., Hu, D., Gough, P. J., Bertin, J., Melnick, A., Kohanbash, G., Bao, R., Lucas, P. C., McAllister-Lucas, L. M.. 2024-09-27. MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression. https://doi.org/10.1101/2024.09.26.614808

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