Scientists at the University of Texas MD Anderson Cancer Center led by Filippo Giancotti, MD, PhD, professor of cancer biology reported they have discovered how an aggressive form of prostate cancer called double-negative prostate cancer (DNPC) metastasizes by evading the immune system. The team also reported on the preclinical development of a new therapy which, when given in combination with existing immunotherapies, appears to stop and even reverse metastasis in mouse models. The study appears in Cancer Cell.
“The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in DNPC. In vivo genetic screening identifies CCL2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor-associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis,” the authors wrote.
A catalytic inhibitor of PRC1 cooperates with immune checkpoint therapy to reverse these processes and suppress metastasis in genetically engineered mouse transplantation models of DNPC. These results reveal that PRC1 coordinates stemness with immune evasion and neoangiogenesis and point to the potential clinical utility of targeting PRC1 in DNPC. Indeed DNPC is difficult to treat and frequently arises in patients previously treated with therapies that inhibit androgen receptors (AR), known to spur prostate cancer cells growth.
The research team noted that an epigenetic regulator known as the polycomb repressor complex 1 (PRC1) coordinates the initiation of metastasis by increasing the regenerative capacity of metastatic cells and by suppressing the immune system and spurring tumor blood vessel growth or angiogenesis.
“The findings open up potential new approaches to treating DNPC, which has been recognized recently as a new subtype that emerges at least in part in response to treatment with next-generation AR inhibitors,” said lead author, Dr. Giancotti, “We showed that PRC1 plays a role with immunosuppression at metastatic sites in DNPC, and we developed a novel in-class inhibitor of PRC1. This inhibitor exhibited efficacy as a single treatment and cooperated with double checkpoint immunotherapy to completely suppress metastasis in preclinical DNPC models.”
Through in vivo genetic screening, the team identified a cytokine called CCL2 as the major pro-metastatic gene induced by PRC1. CCL2 binds to a tumor cell receptor called CCR4 to boost regenerative capacity and to CCR2 in immune cells, creating an immunosuppressive microenvironment and boosting tumor blood vessel growth.
“CCL2 also attracts tumor-associated macrophages and regulatory T cells (Tregs), which suppresses the immune system and stimulates angiogenesis,” continued Giancotti. Their study showed that targeting PRC1 inhibits recruitment of TAMS and Tregs, suppressing tumor metastasis. Giancotti and his research team combined PRC1 with two types of immunotherapy agents, which attracted important immune cells called CD4 and CD8 T cells, resulting in “maximal induction” of tumor cell death in mice. The study indicates that the inhibiting TAMS and Tregs with PRC1 inhibitors enables double checkpoint therapy to not only recruit but also to activate T cells, thus causing metastasis regression..
Su W, Han HH, Wang Y, Zhang B, Zhou B, Cheng Y, Rumandla A, Gurrapu S, Chakraborty G, Su J, Yang G, Liang X, Wang G, Rosen N, Scher HI, Ouerfelli O, Giancotti FG. The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression. Cancer Cell. 2019 Jul 2. pii: S1535-6108(19)30300-9. doi: 10.1016/j.ccell.2019.06.009.