University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
Immunotherapy is a type of treatment that harnesses a patient’s immune system to target diseases like cancer. Chimeric antigen receptor (CAR)-T cell therapy relies on T cells engineered to target antigens expressed on cancer cells and has radically improved treatment for some hematological cancers and is gaining traction in solid tumors. For CAR-T cell therapy to be effective, cancers must express the appropriate antigen. B7-H3 is an immunosuppressive protein often expressed by cancer cells that is targetable with B7-H3.CAR-T cell therapy. Obesity-derived inflammatory signals promote tumor growth, dampen antitumor immunity, and promote expression of immunosuppressive proteins. However, the potential for obesity to alter efficacy of CAR-T cell therapy is unknown. Hence, we sought to understand whether obesity affects activity and durability of B7-H3.CAR-T cell therapy, and whether obesity relies on the immunosuppressive protein, B7-H3, for triple-negative breast cancer (TNBC) growth.We utilized preclinical models to determine the relationship between obesity-associated cytokine signaling and B7-H3. We discovered that cytokines like TNF and IFNγ upregulate B7-H3 in both human and murine TNBC cell lines. We used B7-H3 suppressed cells to determine that obesity promotes TNBC growth by suppressing antitumor immunity through B7-H3 expression. Next, we demonstrated that obesity impairs both B7-H3.CAR-T cell therapy activity and durability. We showed that B7-H3.CAR-T cell therapy can control tumor growth in a syngeneic model of TNBC and that despite similar in vitro cell killing activity, T cells from obese mice harbor important transcriptomic and phenotypic differences. We also show that obesity impairs the formation of tissue-resident memory-like T cells and that obesity is detrimental to survival following rechallenge. Taken together this work demonstrates that obesity is an important but understudied determinant of B7-H3.CAR-T cell therapy response and durability, thus paving the way for future research to study obesity as a variable in large scale clinical immunotherapy settings.Doctor of Philosoph
