Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression

Gamage, H. E. V.; Shahoei, S. H.; Albright, S. T.; Wang, Y.; Smith, A. J.; Farmer, R.; Fink, E. C.; Jacquin, E.; Weisser, E.; Bautista, R. O.; Henn, M. A.; Schane, C. P.; Nelczyk, A. T.; Ma, L.; Das Gupta, A.; Bendre, S. V.; Nguyen, T.; Tiwari, S.; Krawczynska, N.; He, S.; Tjoanda, E.; Chen, H.; Sverdlov, M.; Gann, P. H.; Boidot, R.; Vegran, F.; Fanning, S. W.; Apetoh, L.; Hergenrother, P. J.; Nelson, E. R.

doi:10.1101/2023.08.14.553229

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bioRxiv · 10.1101/2023.08.14.553229

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression

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Abstract

Immune checkpoint blockade (ICB) has revolutionized cancer therapy but has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. We demonstrate that NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the NLRP3 inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Loss of NR0B2 increased mammary tumor growth and metastasis. Small molecule agonists, including one developed here, reduced Treg expansion, reduced metastatic growth and improved the efficacy of ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells providing proof-of-principle that this cholesterol-homeostasis axis may have utility in enhancing ICB. Brief SummaryImmune therapy has been disappointing for breast cancer. NR0B2 within myeloid immune cells reduces the expansion of Tregs, a highly immune suppressive subtype historically challenging to target. NR0B2 within myeloid immune cells represses the inflammasome, leading to reduced Treg expansion and subsequent tumor growth/metastasis. Activation of NR0B2 with small molecule agonists, including one developed herein, attenuates tumor growth and metastasis in murine models of mammary cancer.

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Gamage, H. E. V., Shahoei, S. H., Albright, S. T., Wang, Y., Smith, A. J., Farmer, R., Fink, E. C., Jacquin, E., Weisser, E., Bautista, R. O., Henn, M. A., Schane, C. P., Nelczyk, A. T., Ma, L., Das Gupta, A., Bendre, S. V., Nguyen, T., Tiwari, S., Krawczynska, N., He, S., Tjoanda, E., Chen, H., Sverdlov, M., Gann, P. H., Boidot, R., Vegran, F., Fanning, S. W., Apetoh, L., Hergenrother, P. J., Nelson, E. R.. 2023-08-14. Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression. https://doi.org/10.1101/2023.08.14.553229

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