Targeting MAL2-mediated endocytosis to enhance tumor cell antigen presentation

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Project Abstract Cancer immunotherapy is a promising approach for cancers with no or limited specific targeted therapies. Various forms of immunotherapy, including checkpoint blockade immunotherapies, are proving to be effective by boosting T cell-mediated immune responses. These therapies lead to marked and sustained clinical responses, but only in a limited number of patients and cancer types. Anti-tumor immune responses require functional presentation of tumor antigens and a microenvironment that favors competent immune effectors. To execute the cytotoxicity on cancer cells, the CD8+ cytotoxic T lymphocytes (CTLs) recognize tumor antigens presented on the major histocompatibility complex class I (MHC-I) complex of the cancer cell and trigger the cancer cell to undergo programmed cell death. To evade immune surveillance, cancer cells employ various mechanisms to downregulate the expression of MHC-I molecules or other proteins directly or indirectly involved in antigen processing and presentation. Downregulation appears to be more common than complete elimination of MHC-I expression because the latter renders cancer cells susceptible to the action of natural killer (NK) cells. Increased antigen presentation on tumor cells can be of therapeutic significance since it makes tumor cells more susceptible to the CTLs. In the preliminary study, we identified a membrane protein, MAL2, as an important player that reduces the antigen presentation on breast cancer cells and suppresses the cytotoxicity of tumor-infiltrating CD8+ T cells. To facilitate the preclinical studies for MAL2 inhibition, we have generated monoclonal antibodies against the mouse MAL2. We will test the antitumor effect of MAL2 inhibitor (MAL2 mAb) in mouse breast tumor models. We will also determine the therapeutic activity of MAL2 inhibitor in enhancing the efficacy of immune checkpoint blockade immunotherapy.