Enhancing therapeutic vaccination in melanoma by alleviating STAT3-mediated immune suppression

Despite the fact that the immune system is able to recognize and kill tumor cells, immunotherapy rarely induces objective tumor regression. It has become clear that inhibitory cell types, such as myeloid-derived suppressor cells (MDCSs), are crucially involved in dampening effector Tcell functions. Although the main site of action for MDSCs is most likely the tumor, so far the study of these cells has been largely restricted to the spleen. Therefore, we first compared the suppressive capacity and suppressive mechanisms used by splenic and tumor-derived MDSCs in different mouse tumor models. We showed that tumor-infiltrating MDSCs possess a stronger suppressive capacity than non-infiltrating MDSCs and that various suppressive mechanisms, including a higher nitrite production and arginase activity, account for this differences. Given the important role these MDSCs play in the suppression of antitumor immune responses, different drugs are being developed to specifically target this cell population in order to alleviate their immunosuppressive function. In a second study we investigated the effects of AZD1480, a potent competitive small-molecule inhibitor of JAK1/2 kinases, on the function of different immune cell populations in a melanoma model. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system, including an enhanced suppressive capacity of MDCSs and an impaired proliferation and cytokine secretion of T cells. Taken together, caution should be taken when treating cancer patients with JAK-STAT inhibitors, especially when combining them with immunotherapy.