The FBW7-MCL-1 axis is key in M1 and M2 macrophage-related colon cancer cell progression: validating the immunotherapeutic value of targeting PI3Kγ

초록

Cancer treatment: turning the tide against colon cancer Drugs that target a specific subset of immune cells could render colorectal tumors more susceptible to immunological destruction by the host. The cellular composition of a tumor profoundly affects the odds of progression or survival, and some immune cell types can stall the antitumor response rather than strengthening it. Researchers led by Yong Beom Cho of Sungkyunkwan University, Seoul, South Korea, explored the impact of various subpopulations of macrophages, cells that help coordinate the immune counterattack against cancer. The researchers learned that the relative balance between M2 and M1 subtypes of macrophages correlates with colorectal cancer outcomes, patients with less M2 and more M1 activity generally faring better. They also uncovered a strategy for inhibiting M2 activity, which unleashes a more-aggressive response against the tumor and could thus offer a useful therapeutic approach. Colorectal cancer is a devastating disease with a low 5-year survival rate. Recently, many researchers have studied the mechanisms of tumor progression related to the tumor microenvironment. Here, we addressed the prognostic value of tumor-associated macrophages (TAMs) using a total of 232 CRC patient tissue samples and investigated the mechanisms underlying TAM-related colon cancer progression with respect to PI3K gamma regulation using in vitro, in vivo, and ex vivo approaches. Patients with M2/M1 < 3 had significantly improved progression-free survival and overall survival compared with patients with M2/M1 > 3. M1 and M2 macrophages elicited opposite effects on colon cancer progression via the FBW7-MCL-1 axis. Blocking macrophage PI3K gamma had cytotoxic effects on colon cancer cells and inhibited epithelial-mesenchymal transition features by regulating the FBW7-MCL-1 axis. The results of this study suggest that macrophage PI3K gamma may be a promising target for immunotherapy in colon cancer.

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