Cell-Nonautonomous ER Stress-Mediated Dysregulation of Immunity by Cancer Cells

The immune surveillance hypothesis posits that neoantigens presented by tumor cells are detected by the immune system and eliminated, keeping tumor formation and growth at bay. Operationally this requires that tumor cells be taken up by local sentinels of the immune system, myeloid antigen presenting cells, which then proceed to present tumor associated antigens to T cells, resulting in specific rejection of tumor cells. Yet, one of the central unsolved paradoxes of tumor immunology is how the tumor escapes immune control which is reflected in the lack of effective autochthonous or vaccine-induced anti-tumor T cell responses.In this chapter we discuss the emerging new idea that the endoplasmic reticulum (ER) stress response/unfolded protein response (UPR) activated in response to tumor microenvironmental noxae, acts not only as a key cell-intrinsic regulator of tumor growth and survival, but also as a central cell-extrinsic modulator of myeloid cell and T cell function. We will review the cellular and molecular basis of the anti-tumor immune response and the polarization of myeloid cells and T cells and place these into a UPR-centered perspective. We will also present the UPR as a cell-extrinsic regulator of anti-tumor immunity, effected by the newly-discovered "transmissible" ER stress