Suppressing the Co-chaperone UNC45A reprograms the immunosuppressive tumor microenvironment to fight Cancer

Abstract Breast cancer remains one of the leading causes of death among women in the US. When available, targeted therapies have significantly improved the outcomes for breast cancer patients. Unfortunately, resistance to therapies and relapses are common, especially among patients with triple-negative breast cancer (TNBC), a

particularly aggressive disease for which limited target therapy options are available. It is becoming clear that the immunosuppressive tumor microenvironment (TME) is a major obstacle to successfully treating aggressive breast cancers. Tumor growth is associated with the accumulation of immunosuppressive cells in the TME,

causing cytotoxic T-cell dysfunction and tumor escape. Furthermore, tumor cells activate escape mechanisms such as triggering the expression of the immune checkpoint PD-L1, which reduces CD8+ T cell killing. Indeed, immunotherapeutic agents targeting PD-L1, and other immune checkpoint molecules, have shown remarkable

efficacy in metastatic tumors refractory to standard protocols. Unfortunately, only a small subset of patients responds to these immunotherapies. Therefore, there is an urgent need for improved therapeutic strategies. Discovering new immunotherapeutic targets and innovative combinations with existing therapies are attractive

options for expanding the benefits of engaging the immune system against cancer. We discovered that during breast tumorigenesis, the Hsp90 co-chaperone UNC45A becomes more nuclear and essential for cancer cell division but remains dispensable for normal cell proliferation. Further, we found that suppressing UNC45A in

mouse syngeneic TNBC tumors triggers a drastic reprogramming of the immune-suppressive TME into a more immune-responsive one. In addition, loss of UNC45A hampers the ability of cancer cells to repair ionizing radiation (IR)-induced DNA damage and sensitizes in vivo TNBC models to radiation therapy. In this application,

we propose that UNC45A is a promising novel immunotherapeutic target and that its inhibition, in combination with IR therapy, will reduce the TNBC burden. Our Specific Aims are 1. To characterize TME reprogramming caused by loss of UNC45A in malignant cells; 2. To define the molecular mechanism by which

UNC45A promotes an immunosuppressive TME; 3. To determine the therapeutic potential of UNC45A inhibition in combination with IR therapy.