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.
This study is aimed at unveiling new molecular mechanisms that regulate cancer cell survival, the reactivation of gammaherpesviruses from latency and more importantly the cross-talk between cancer cells and immune cells such as DCs and macrophages. These immune cells that play a pivotal role in initiating and regulating immune response aginst new antigens such as tumor and viral antigens can be transformed by tumors or oncoviruses-infection into cells that sustain instead of fight cancer. Indeed counteracting cancer-induced immune suppression and instigating an effective anti-cancer immune response seems to hold a great promise in anti-cancer therapy. It seems that ER stress could be transfered from tumor cells to immune cells and induce immune dysfunction. These findings are in contrast with others showing that ER strees/UPR activation in tumor cells helps to expose or release immune activating DAMPs suggesting that much remain to be clarified in the cross-talk between cancer and immune cells. A special focus in this project will be given to the correlation of UPR activation, release of immune suppressive soluble factors and PD-L1 expression either in tumor cells and in immune cells exposed to tumor released factors or infected by gammaherpesviruses such Epstein Barr and Kaposi's Sarcoma viruses. As PD-L1 expression exerts a strong inhibitory effect on T cell response, the finding of molecular mechanisms that regulate its expression will help to counteract oncovirus- as well as cancer-induced immune suppression and likely improve anti-cancer treatments. Interestingly, in a previous study we have demonstrated that the activation of pathways such as STAT3 and NFkB were involved in EBV-mediated PD-L1 up-regulation in infected monocytes. New preliminary results suggest that UPR activation could play a role in the up-regulation of PD-L1 expression on the surface of dendritic cells exposed to tumor-released factors of infected by the other human gammaherpesvirus KSHV, suggesting that is worth to further investigate whether the inhibition of ER stress and which UPR sensor inhibition could be exploited in combination with chemotherapies or even with humanyzed anti-PD-L1 antibody to improve the outcome of anti-cancer chemotherapies.