The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD1 address these issues in part, clinical responses remain limited to a subpopulation of patients. Recently, we identified interleukin-34 (IL-34) produced by lung cancer cells as a driver of chemoresistance. In particular, we found that IL-34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant lung cancer cells by activating AKT signaling. Targeting IL-34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy. We have further observed that the expression of IL-34 in other solid and hematological cancers. Our data define a novel pathogenic role for IL-34 in mediating immunosuppression and chemoresistance and identify it as a tractable target for anticancer therapy.
Baghdadi, et al. Chemotherapy-induced IL-34 enhances immunosuppression by tumor-associated macrophages and mediates survival of chemoresistant lung cancer cells. Cancer Res 76: 6030-6042, 2016
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