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Oerum-Madsen, Maj Sofie

University of British Columbia

Pediatric solid tumors often present with a non-permissive cold immune cell microenvironment that contributes to immunotherapy resistance. Being a major component and active player in the cancer cell glycocalyx and microenvironment, glycosaminoglycans (GAGs) such as chondroitin sulfate (CS) assist in essentially all hallmarks of cancer, making CS an attractive target in cancer. Although abnormal presentation of CS in cancer is well-established, little is known about its regulation in cancer. This thesis describes two distinct, but related projects. The first project investigated the regulation and functional impact of GAGs, particularly CS, during endoplasmic reticulum (ER) stress in cancer cells. Quantitative and qualitative analyses of GAGs revealed an altered GAG architecture in osteosarcoma cells in response to ER stress with 4-O-sulfated CS levels increasing upon pharmacologically induced ER stress compared to controls. Using cells engineered to display distinct GAG repertoires, we showed that 4-O-sulfated CS protects cells from apoptosis during prolonged ER stress, regulates cellular oxidative homeostasis, and supports the adaptive expression of GRP78, a master regulator of the unfolded protein response. Altogether, we report that perturbations in the ER homeostasis trigger CS biosynthesis, suggesting that these pathways are linked. A distinct type of 4-O-sulfated CS in the placenta functions as a receptor for the Plasmodium falciparum lectin, VAR2CSA, during pregnancy-associated malaria. Due to the similarities to 4-O-sulfated CS in solid tumors, termed oncofetal CS (ofCS), the malaria VAR2CSA-4-O-sulfated CS binding-module can be exploited for cancer targeting. The second project describes the development of a novel type of bispecific immunotherapy for pediatric solid tumors based on the ability of recombinant VAR2CSA (rVAR2) to target ofCS in pediatric solid tumors. We engineered an interleukin-2 variant (IL-2v) genetically fused to rVAR2 (ILVAR) to specifically bind ofCS on the surface of cancer cells via rVAR2, while engaging immune effector cells via IL2v. We demonstrated that the distinct molecular constituents of ILVAR are functional, thereby enabling anti-cancer cytotoxicity in pre-clinical tumor models. Collectively, the data serve as a proof-of-concept for further evaluating the feasibility of using ILVAR to activate targeted immune responses within the ofCS-positive tumor microenvironment of pediatric cancers.

Text

2024-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79565

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/