DATE: November 14, 2017
TIME: 10:00am PST, 1:00pm EST

Successful tumor outgrowth requires the coordination of a variety of cell intrinsic and cell extrinsic signaling events. These events include those establishing a tumor microenvironment (TME) that both enables tumor cell survival and disables anti-tumor immunity. Recent reports demonstrate that these events require molecules produced by resident tumor cells. Tumor-borne signals within the tumor microenvironment propagate tumor cell fitness and immune hijacking. The endoplasmic reticulum (ER) stress is an adaptive response to a variety of TME insults, including hypoxia and nutrient deprivation, raising the possibility that ER stress could serve as a potential source of tumor cell fitness and immune dysregulation. To that end, we induced cancer cells of various origin to undergo ER stress and harvested the resulting conditioned medium (CM) to explore its effects on both recipient cancer cells and immune cells. Cell culture medium became an invaluable tool to our studies as it allowed us to recreate stimuli existent within the tumor microenvironment under controlled conditions. Our results revealed that the CM of cancer cells undergoing ER stress transmits ER stress to recipient cells. On the one hand, myeloid cells (macrophages and dendritic cells) treated with the CM of ER stressed cancer cells acquire a mixed pro-inflammatory and immune suppressive phenotype, which restrained T cell anti-tumor immunity and facilitated tumor growth in vivo. On the other hand, cancer cells treated with the CM of ER stressed cancer cells acquire cellular fitness to a variety of challenges including nutrient deprivation and chemotherapies. When implanted into immune competent hosts, ER stress experienced cancer cells grew at markedly faster rates than inexperienced ones. These findings support the existence of a novel mechanism used by tumor cells to restrain anti-tumor immunity while enhancing cellular fitness with the TME.

Learning Objectives:

• Understand how to design an in vitro system to model phenomenon within the tumor microenvironment
• Understand how ER stress in cancer cells may facilitate immune dysregulation and chemoresistance in vivo