New research reveals how a cancer-associated protein enables tumor cells to evade the immune system by both suppressing antitumor influences and promoting tumor-enhancing conditions, in essence turning the immune system to the dark side of the force. The study is published by Cell Press in the February 3rd issue of the journal Cancer Cell.

Continuous activation of the transcription factor Stat3 contributes to the survival and proliferation of cancer cells. Activated Stat3 suppresses antitumor activity by stimulating immunosuppressive factors and by inhibiting expression of chemicals that are critical for antitumor immunity. In addition to tumor cells themselves, Stat3 is activated in many different types of immune cells present in the tumor microenvironment, such as macrophages and dendritic cells, facilitating the crosstalk between tumor cells and tumor-associated immune cells.

Recent research has suggested that the cytokine IL-23 has tumor-promoting effects while the closely related cytokine IL-12 has anti-tumor characteristics. "Although results from previous studies have suggested that IL-23 and IL-12 may play opposite roles in cancer progression, the specific mechanisms of action in tumor regulation have not been elucidated," explains study author Dr. Drew Pardoll from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine.

Drs. Hua Yu, Marcin Kortylewski and Hong Xin from the Beckman Research Institute at City of Hope in Duarte, California and Dr. Pardoll, investigated how IL-23 and IL-12 are differentially regulated in the tumor microenvironment. The researchers found that Stat3 induced expression of IL-23 in tumor-associated macrophages and inhibited expression of IL-12 in tumor-associated dendritic cells.

Unexpectedly, IL-23 receptor was upregulated in regulatory T cells within the tumor microenvironment and enhanced their immunosuppressive activity. In these cells, the IL-23 receptor activates Stat3 and leads to production of the immunosuppressive cytokine IL-10.

Taken together, these findings demonstrate that Stat3 promotes IL-23-related pro-cancer immune responses and concurrently inhibits IL-12-dependent antitumor immunity. "Because Stat3 is a point of convergence for signaling pathways commonly activated in cancer, our data reveal a mechanism by which oncogenic pathways regulate the immune microenvironment to promote tumor development," concludes Dr. Yu.



The researchers include Marcin Kortylewski, Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA; Hong Xin, Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA; Maciej Kujawski, Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA; Heehyoung Lee, Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA; Yong Liu, Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA; Timothy Harris, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD; Charles Drake, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD; Drew Pardoll, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD; and Hua Yu, Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA.