Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response

Abstract

Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice. We then established that only cotreated cells induced an efficient tumor-specific T-cell activation ex vivo and that tumor antigen-specific T cells could only be isolated from cotreated animals. In addition, only when mice were immunized with cotreated dead tumor cells could they be protected (vaccinated) from a subsequent challenge using the same tumor in viable form. Finally, we demonstrated that this effect was at least partially mediated through ERp57/calreticulin exposure on the plasma membrane. These data identify that the targeting of glycolysis can convert conventional tolerogenic cancer cell death stimuli into immunogenic ones, thus creating new strategies for immunogenic chemotherapy.

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

“…1 Nonetheless, at least some anticancer agents display an optimal efficacy in the presence of an intact immune system, but not when mice lack T cells, dendritic cells (DCs), several other effectors of innate and adaptive immunity or when they are treated with a CD11b-specific antibody that blocks the extravasation of DC precursors. [2][3][4][5][6] These results point to a hitherto poorly understood role for anticancer immune responses in determining the long-term success of chemotherapy, a notion that is in line with abundant clinical data indicating that tumor infiltration by cytotoxic T lymphocytes influences disease outcome. [7][8][9][10] Cancer cells respond to some chemotherapeutics such as anthracyclines and oxaliplatin by undergoing an immunogenic form of cell death, meaning that such dying cells become able to induce a potent cellular immune response on subcutaneous injection into immunocompetent mice.…”

“…The pre-apoptotic exposure of CRT at the cell surface has emerged as an important hallmark of ICD, meaning that it can predict -at least in part -the capacity of dying cells to elicit a protective anticancer immune response, both in rodent models 2,13,14,17,18,33,34 and in patients. [35][36][37] Here, we report the unexpected finding that CRT exposure is regulated not only by cell-intrinsic mechanisms, but also by soluble factors that operate in an autocrine/paracrine manner.…”

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

“…Excessive ROS are detrimental; therefore, increasing ROS generation and simultaneously attenuating detoxification can kill cancer cells [50].…”

Consensus guidelines for the detection of immunogenic cell death

“…22 It turned out that the unsuspected ability of doxorubicin (an anthracycline employed for the treatment of various carcinomas) to trigger ICD as a standalone intervention, hence converting dying cancer cells into a vaccine that is efficient in the absence of adjuvants, is shared by a relatively restricted set of lethal triggers. [28][29][30][31][32][33] These include, but perhaps are not limited to, mitoxantrone and epirubicin (2 other anthracyclines currently used in the clinic), [34][35][36][37] bleomycin (a glycopeptide antibiotic endowed with antineoplastic properties), 38 oxaliplatin (a platinum derivative generally employed against colorectal carcinoma), [39][40][41][42] cyclophosphamide (an alkylating agent approved for the treatment of neoplastic and autoimmune conditions), [43][44][45][46][47][48] etoposide (a topoisomerase inhibitor currently used for the treatment of several neoplasms) combined with the chemical inhibitor of glycolysis 2-deoxyglucose, 49,50 patupilone (a microtubular inhibitor that has not yet been approved for use in humans), [51][52][53] septacidin (an antifungal antibiotic produced by Streptomyces fibriatus) 54,55 specific forms of radiation therapy, 34,[56][57][58][59][60][61][62][63][64] photodynamic therapy (a clinically approved antican...…”