Abstract Targeting immune checkpoint signaling with blocking antibodies has reached a limitation in the treatment of advanced cancers. Although antibodies that bind programmed death ligand 1 (PD-L1) are effective in blocking PD-L1's extracellular interaction with PD-1 receptor on T cells, the potential adaptive upregulation of PD-L1 and its recycling from intracellular compartment to the cell surface may compromise their efficacy. Importantly, the discovery of PD-L1's intracellular functions in cancer cells to promote thier survival and metabolism also highlight a mechanism by which tumor cells can gain resistance to cytotoxic therapy and call for a new strategy to target PD-L1. There is therefore a critical need to design, test, and translate new agents that can simultaneously inhibit PD-L1's extracellular and intracellular functions. This application will utilize a new PD-L1 antibody (clone H1A) that can reduce the expression of PD-L1 in tumor cells through disrupting the association of PD-L1 with CMTM6 (a molecule that can stabilize PD-L1 recycling and expression) and subsequently directing PD-L1 for degradation. H1A-induced degradation of PD-L1 may not only disrupt PD-1/PD-L1 interactions due to the loss of PD-L1, thus removing PD-1's suppressive signals in T cells, but also disrupt PD-L1's cell-intrinsic functions within tumor cells and myeloid cells, thereby decreasing tumor resistance to chemotherapy and releasing the immune-stimulatory function of myeloid cells. Thus, H1A antibody may be a good candidate for targeting the dual functions of PD-L1 for cancer therapy. Based on preliminary data, the central hypothesis of this proposal is that intracellular signaling through PD-L1 results in tumor resistance to cytotoxic chemotherapy and limits the immune-stimulatory function of myeloid cells. Thus, targeted agents that result in degradation of PD-L1 and elimination of its intracellular signaling ability represent a novel therapeutic strategy that will both synergize with chemotherapy and improve the immune response. This hypothesis will be tested by pursuing two specific aims: (1) Determine how H1A antibody synergizes with chemotherapy to overcome tumor resistance; (2) Determine how H1A antibody promotes an enhanced T cell response to attack tumors. To further assess the future clinical use of H1A antibody, a fully humanized version of H1A and humanized PD-1 and PD-L1 mice have been produced, which will allow for evaluation of the therapeutic effects of H1A either alone or in combination with chemotherapy and exploration of H1A's new mechanism of action in vivo. The overall impact of the proposed research is high because it will provide a new therapeutic agent that is capable of targeting the dual functions of PD-L1, resulting in improved efficacy of cytotoxic chemotherapy and an enhanced immune response. This strategy represents a significant paradigm shift within the field in terms of how to target immune checkpoint molecules like PD-L1 for future clinical applications.
- National Cancer Institute: $363,713.00
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