Low dose chemotherapy potentiates Cancer Immunotherapy, through IFNg signaling pathway
Shabnam Shalapour1, Weihua Li1, Michael Karin1
1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093
Cancer is characterized by accumulation of genetic alterations and loss of normal cellular regulatory processes. These events result in expression of tumor-associated and tumor-specific antigens, which may activate anti-cancer immune responses. However, the tumor microenvironment induces T cell tolerance, thereby contributing to uncontrolled tumor growth. Two main classes of immune checkpoint inhibitors were found to be effective in human cancer: CTLA-4 targeting agents, namely CTLA-4 blocking antibodies, and PD-1/PD-L1 signaling inhibitors, which include anti-PD-1 and anti-PD-L1 antibodies. Despite the excitement and new therapeutic frontiers unraveled by these agents, response rates rarely exceed 40-50% and are more commonly around 20% in those situations where checkpoint inhibitors are deployed as single agents. One way to increase the efficacy of checkpoint inhibitors is to combine them with immunogenic cytotoxic therapies, including ionizing radiation and chemotherapy, which enhance antigen release and presentation. But exactly how such therapies accomplish their immunogenic effects is far from understood. Curiously, only certain chemotherapeutic agents exhibit immunogenic activity when used at low doses, including Oxaliplatin (Oxali), mitoxanthrone (Mito), cyclophosphamide (Cyclo). Moreover, structurally related compounds, such as Cisplatin (Cis), can be completely devoid of immunogenic activity. The basis for such functional differences is unknown, as both Oxali and Cis are equipotent in their ability to induce apoptotic and necrotic cancer cell death. It was suggested that the main difference in the immunogenic activity of these drugs pertains to their ability to induce autophagic cell death, and support the cross-priming of CTLs. We found that Oxali induced the IFNR2 expression in PCa cells and Melanoma cells. Furthermore, combined Oxali and IFN treatment increased the amount of activated STAT1, P-STAT1, indicating increased IFN response which also regulates the responsiveness to checkpoint inhibitors and tumor cell killing, involving upregulation of class I MHC molecules and stimulation of antigen-presentation by tumor cells. In agreement with this finding the immunoproteasome subunits LMP2 and LMP7 expression were also increased after Oxali treatment in tumor cells. In summary, our data shows a new mechanism through which immunogenic cytotoxic therapies might increase the response to immunotherapy.
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