Discovery shows how difficult prostate cancer is to escape the immune system

Researchers at the MD Anderson Cancer Center at the University of Texas discovered how an aggressive form of prostate cancer, called double-negative prostate cancer (PCN), metastasized by avoiding the immune system. The researchers also reported the preclinical development of a new treatment that, combined with existing immunotherapies, appears to stop and even reverse metastasis in mice.

DNPC is difficult to treat and occurs frequently in patients previously treated with androgen receptor (AR) inhibitory therapies, known to stimulate the growth of prostate cancer cells. The results of the study were published in the July 18th online edition of Cancer cell.

Filippo Giancotti, MD, Ph.D., professor of cancer biology, announced that an epigenetic regulator called polycomb repressor complex 1 (PRC1) coordinates the initiation of metastasis by increasing the regenerative capacity of cells metastatic and suppressing the immune system. stimulate tumor growth of blood vessels or angiogenesis.

"The results open up new potential approaches for the treatment of DNPC, which has recently been recognized as a new subtype emerging, at least in part, in response to treatment with novel AR inhibitors", said Giancotti, "We have shown that PRC1 plays a role with immunosuppression at metastatic sites in DNPC, and we have developed a new inhibitor of PRC1 in the clbad.This inhibitor has shown its efficacy as a unique treatment and has cooperated with dual-point immunotherapy to completely suppress metastases in preclinical DNPC models. "

Through in vivo genetic screening, the team identified a cytokine called CCL2, which is the major PRC1-induced pro-metastatic gene. CCL2 binds to a tumor cell receptor called CCR4 to increase the regenerative capacity and to CCR2 in immune cells, creating an immunosuppressive microenvironment and stimulating the growth of tumor blood vessels.

"CCL2 also attracts tumor-badociated macrophages (TAMS) and regulatory T cells (Tregs), which suppress the immune system and stimulate angiogenesis," Giancotti said. "Our study showed that targeting PRC1 inhibits TAMS and Treg recruitment, thereby suppressing tumor metastasis."

The Giancotti team badociated PRC1 with two types of immunotherapy agents, which attracted important immune cells called CD4 and CD8 T cells, resulting in a "maximal induction" of the death of tumor cells in the mouse.

"This indicates that inhibition of TAMS and Tregs with PRC1 inhibitors allows dual control therapy to recruit but also activate T cells, thereby causing regression of metastases," Giancotti said. .

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