Mechanism of resistance to cancer immunotherapy
See manuscript in Science (Jan 2018)
A genome-scale gRNA library is introduced into a tumor cell line that expresses Cas9. Selection is then performed with tumor-specific T cells compared to control T cells. Depleted gRNAs represent resistance genes because inactivation of these genes results in more effective T cell-mediated cytotoxicity.
See manuscript in Science (Jan 2018)
A genome-scale gRNA library is introduced into a tumor cell line that expresses Cas9. Selection is then performed with tumor-specific T cells compared to control T cells. Depleted gRNAs represent resistance genes because inactivation of these genes results in more effective T cell-mediated cytotoxicity.
Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We have discovered many novel resistance genes in a T cell-based genome-scale CRISPR/Cas9 screen. We discovered a major chromatin regulator that confers resistance, which is the PBAF subtype of the SWI/SNF complex. Inactivation of three genes encoding unique subunits of the PBAF complex (Pbrm1, Arid2 and Brd7) sensitized tumor cells to cytotoxic T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-g, resulting in enhanced secretion of chemokines that recruit effector T cells into the tumor. In a back-to-back paper, clinical colleagues at Dana-Farber demonstrated that inactivating mutations of one of these genes (PBRM1) was significantly associated with better clinical responses to immunotherapy with PD-1/PD-L1 antibodies (Science 2018, 359: 801). In many human cancers, expression of PBRM1 and ARID2 inversely correlates with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas are more strongly infiltrated by cytotoxic T cells. We are now characterizing other novel genes that we discovered as resistance mechanisms, with the goal of identifying novel therapeutic targets that expand the benefit of cancer immunotherapy.
Pan, D., Kobayashi, A., Jiang, P., de Andrade, L.F., Tay, R.E., Luoma, A., Tsoucas, D., Qiu, X., Lim, K., Rao, P. and Long, H.W., 2018. A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing. Science, p.eaao1710.