Ovarian carcinoma is an aggressive cancer that is refractory to standard treatments and all current forms of immunotherapy. Like other aggressive tumors, ovarian tumors have evolved strategies to suppress recognition by the immune system. Dr. Juan Cubillos-Ruiz and his team at Cornell University have shown that the ovarian cancer tumor microenvironment (TME) can inhibit adaptive immunity by provoking an endoplasmic reticulum (ER) stress response in tumor infiltrating T cells through activation of the IRE1α-XBP1 pathway. TME-modulated nutrient restriction of T cells causes an accumulation of misfolded proteins, inducing ER stress that triggers metabolic alterations, changes in chromatin structure, and reduced tumor cell killing. In a first phase ASPIRE project, scientists in the Cubillos-Ruiz lab demonstrated that inhibition of the IRE1α-XBP1 pathway in T cells causes a delay in tumor progression in pre-clinical animal models. Building upon these observations in a second phase ASPIRE project, Cubillos-Ruiz and team will assess the impact of ER stress-induced metabolic changes on T-cell chromatin architecture to determine whether epigenetic reprogramming alters T-cell function. They will complement these analyses by assessing the impact of IRE1α-XBP1 disruption on the efficacy of immune checkpoint inhibitors as well as on the function of ovarian cancer-reactive T-cell therapies introduced into cancer models. The results of these efforts will lay the foundation for development of ER stress response-targeting drugs that could be combined with immunotherapies to improve outcomes in patients with immune-evasive cancers such as ovarian cancer.
PUBLISHED RESEARCH
Mohamed E, Sierra RA, Trillo-Tinoco J, Cao Y, Innamarato P, Payne KK, de Mingo Pulido A, Mandula J, Zhang S, Thevenot P, Biswas S, Abdalla SK, Costich TL, Hänggi K, Anadon CM, Flores ER, Haura EB, Mehrotra S, Pilon-Thomas S, Ruffell B, Munn DH, Cubillos-Ruiz JR, Conejo-Garcia JR, Rodriguez PC. The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling. Immunity. 2020.
Payne KK, Mine JA, Biswas S, Chaurio RA, Perales-Puchalt A, Anadon CM, Costich TL, Harro CM, Walrath J, Ming Q, Tcyganov E, Buras AL, Rigolizzo KE, Mandal G, Lajoie J, Ophir M, Tchou J, Marchion D, Luca VC, Bobrowicz P, McLaughlin B, Eskiocak U, Schmidt M, Cubillos-Ruiz JR, Rodriguez PC, Gabrilovich DI, Conejo-Garcia JR. BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells. Science. 2020.
Montrose DC, Nishiguchi R, Basu S, Staab HA, Zhou XK, Wang H, Meng L, Johncilla M, Cubillos-Ruiz JR, Morales DK, Wells MT, Simpson KW, Zhang S, Dogan B, Jiao C, Fei Z, Oka A, Herzog JW, Sartor RB, Dannenberg AJ. Dietary Fructose Alters the Composition, Localization, and Metabolism of Gut Microbiota in Association With Worsening Colitis. Cell Mol Gastroenterol Hepatol. 2020.
Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021.
Paffenholz SV, Salvagno C, Ho YJ, Limjoco M, Baslan T, Tian S, Kulick A, de Stanchina E, Wilkinson JE, Barriga FM, Zamarin D, Cubillos-Ruiz JR, Leibold J, Lowe SW. Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer. Proc Natl Acad Sci U S A. 2022.
Chae CS, Sandoval TA, Hwang SM, Park ES, Giovanelli P, Awasthi D, Salvagno C, Emmanuelli A, Tan C, Chaudhary V, Julia Casado, Kossenkov AV, Song M, Barrat FJ, Holcomb K, Romero-Sandoval EA, Zamarin D, Pepin D, D’Andrea AD, Farkkila A, Cubillos-Ruiz JR. Tumor-derived Lysophosphatidic Acid Blunts Protective Type-I Interferon Responses in Ovarian Cancer. Cancer Discov. 2022.
Salvagno C, Mandula JK, Rodriguez PC, Cubillos-Ruiz JR. Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity. Trends Cancer. 2022.
Chaudhary V, Ah Kioon MD, Hwang SM, Mishra B, Lakin K, Kirou KA, Zhang-Sun J, Wiseman RL, Spiera RF, Crow MK, Gordon JK, Cubillos-Ruiz JR, Barrat FJ. Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses. J Exp Med. 2022.
Crowley MJP, Bhinder B, Markowitz GJ, Martin M, Verma A, Sandoval TA, Chae CS, Yomtoubian S, Hu Y, Chopra S, Tavarez DA, Giovanelli P, Gao D, McGraw TE, Altorki NK, Elemento O, Cubillos-Ruiz JR, Mittal V. Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer. Nat Commun. 2023.
Di Conza G, Ho PC, Cubillos-Ruiz JR, Huang SC. Control of immune cell function by the unfolded protein response. Nat Rev Immunol. 2023.
Awasthi D, Chopra S, Cho BA, Emmanuelli A, Sandoval TA, Hwang SM, Chae CS, Salvagno C, Tan C, Vasquez-Urbina L, Fernandez Rodriguez JJ, Santagostino SF, Iwawaki T, Romero-Sandoval EA, Crespo MS, Morales DK, Iliev ID, Hohl TM, Cubillos-Ruiz JR. Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis. J Clin Invest. 2023.