Endoplasmic reticulum (ER) stress in immunity
Mounting optimal immune responses against malignant cells and pathogens requires high levels of protein synthesis, folding, modification, and trafficking in leukocytes, which are processes coordinated by the endoplasmic reticulum (ER). However, diverse extracellular and intracellular conditions can affect the protein-handling capacity of this organelle, inducing a state of ‘ER stress’ that activates the unfolded protein response (UPR). Our research has provided key insights into the role of ER stress response pathways in immunity, revealing its context-dependent impact on immune cell metabolism, function, and fate. We uncovered that activation of ER stress sensors can stimulate lipogenesis and prostaglandin biosynthesis in myeloid cells. Further, we established that in T cells experiencing nutrient restriction, the activation of ER stress sensors can regulate mitochondrial function and bioenergetics. Dysregulation of the UPR in immune cells can therefore contribute to various pathologies such as cancer, chronic pain, autoimmunity, inflammation, and metabolic disorders. Targeting abnormal ER stress responses has emerged as a promising approach to control or restore immune cell function in diverse pathological conditions. Our laboratory is interested in answering multiple questions relevant to the role of ER stress in immunity, with an emphasis on defining how the tumor microenvironment causes ER stress in multiple cell populations to evade immune control.
Neutrophils engulfing Candida albicans.
ER stress in host-microbe interactions
Sensing and responding to pathogens can lead to the accumulation of misfolded proteins in the ER of immune cells. Pathogens may also produce factors that alter the protein-folding capacity of the ER in host cells. Both events can provoke “ER stress” and activation of the UPR. Our lab is interested in understanding how ER stress response pathways interplay with innate immune signaling during microbial infections. We recently found that systemic infection with the human opportunistic fungal pathogen Candida albicans causes ER stress and hyperinflammatory IRE1 activation in myeloid cells that promotes fatal kidney damage. We are also interested in defining whether metabolic alterations caused by microbial overgrowth in the intestine can disturb ER homeostasis and activate the host UPR. In collaboration with the group of Dr. Diana K. Morales (dkmolareslab.org), we are exploring the role of host ER stress sensors in pathogen-induced intestinal inflammation and microbial translocation.
Nutrition, metabolism, and anti-tumor immunity
While dissecting the role of ER stress in immunity, our group identified that lysophosphatidic acid (LPA) enriched in the tumor microenvironment blunts anti-cancer immunity driven by type-I interferon (IFN) responses (Cancer Discovery 2022). We also uncovered that high-fat diet-induced obesity causes aberrant fatty acid oxidation (FAO) in DCs, hindering their antigen-presenting capacity (Journal of Immunology, 2022). These findings have ignited a new research direction in our lab that seeks to define how specific dietary elements shape immune cell function in cancer. Moreover, we are interested in exploiting nutrition-based strategies to reprogram anti-tumor immunity and enhance the efficacy of cancer immunotherapy. We focus on metastatic ovarian cancer to develop these important lines of research as it is unknown whether dietary habits contribute to the immune cell dysfunction and immunosuppression frequently observed in metastatic ovarian tumors that do not respond to current forms of immunotherapy.
scRNA-seq analysis of intratumoral immune cells reprogrammed by diet
Unconventional cancer immunotherapies
Immune cell dysfunction and immunosuppression in the tumor microenvironment are major impediments to the success of immunotherapy in the clinic. Our translational research focuses on understanding and targeting the molecular programs that restrain anti-tumor immunity, with the goal of developing new and more effective therapies for patients. We are working on the following projects:
Targeting ER stress sensors to unleash anti-tumor immunity
Our lab uncovered that immunotherapy-resistant malignancies such as ovarian cancer provoke persistent ER stress in infiltrating dendritic cells (DCs) and T cells to evade immune control and promote malignant progression (Cell 2015, Nature 2018). We then discovered that activation of ER stress sensors drives prostaglandin biosynthesis, promoting pain perception under inflammatory conditions (Science 2019) while orchestrating immunosuppression in lung tumors (Nat Commun 2023). These findings have offered novel opportunities for therapeutic intervention as well as new mechanistic understanding of key sources immune regulation in cancer (Nat Rev Cancer 2021). Hence, we are developing innovative gene therapy and pharmacological approaches to control the abnormal activation of ER stress sensors and relieve immunosuppression in the tumor microenvironment.
Rewiring intratumoral immune cells through selective TLR stimulation
We found that leukocytes that normally reside in the peritoneal cavity can be trained to induce potent and durable immunity to metastatic ovarian cancer. We are currently dissecting how in situ TLR stimulation boosts the protective activity of these immune cells, transforming them into local “first responders” that intercept early ovarian cancer dissemination to other organs such as the omentum.
B cells (brown) infiltrating ovarian cancer metastatic lesions
Transmission electron micrographs of cancer cells undergoing stress during iron deprivation.
Modulating iron metabolism to awaken innate immunity to cancer
Dysregulated iron accumulation in tumors has been shown to facilitate malignant progression and therapy resistance. Ovarian cancer cells are addicted to iron and therefore have developed multiple strategies to accumulate this element in the tumor microenvironment as a mechanism of survival. We are interested in understanding how iron accumulation in cancer cells facilitates the establishment of immunosuppressive programs in tumors. We are also employing diverse genetic and pharmacologic approaches to control this process and enhance anti-tumor immunity.
FUNDING
Our research has been funded by the U.S. National Institutes of Health, the U.S. Department of Defense, AACR-Stand Up to Cancer, the Cancer Research Institute, the Pershing Square Sohn Cancer Research Alliance, The Mark Foundation for Cancer Research, the Mary Kay Foundation, the Ovarian Cancer Research Alliance, and Weill Cornell Medicine. We are very grateful to these organizations for their generous and continued support.
