Ricerc@Sapienza

Tumor cells do not live as not isolate entities but interact with other cells in the tumor environment such as fibroblasts and myeloid immune cells. Regarding the latter, tumor cells not only render them dysfunctional in order to escape from immune recognition but co-opt them to sustain tumor survival and progression. Among the strategies through which tumors do so, they promote the transformation of macrophages and DCs into Tumor Associated Macrophages (TAM) and myeloid-derived suppressor cells (MDSCs) by releasing soluble factors such as cytokines and oxidant species. Moreover, cancer cells up-regulate the immune check point inhibitors i.e. PD-L1 on their surface as well as on the surface of antigen presenting cells present in the tumor environment. PD-L1 by interacting with PD-1 expressed on T cell surface induces T cell exhaustion, strongly impairing immune response. As PD-L1 up-regulation represents an important immune-escape mechanism, strategies aimed at inhibiting it have been introduced in the clinical practise to more successfully treat cancer patients. ER stress and UPR activation in cancer cells has been reported to promote immune dysfunction in the tumor environment, therefore in this study, we will investigate how the activation of the different UPR arms in tumor cells treated or not with chemotherapies could influence the release of factors leading to immune dysfunction and PD-L1 expression on the surface of tumor cells. The UPR activation and PD-L1 expression on their surface will be also evaluated in myeloid immune cells (DCs and macrophages) exposed to tumor released factors. The inhbition of the different arms of UPR will be correlated with the immune funcion of these cells in terms of phagocitic and allostimulatory capacity and cytokine release.