Targeting CD5 on Tumor-associated T and B cells to improve PD-1 blockade in Breast Cancer

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PROJECT SUMMARY / ABSTRACT Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer that has a poor prognosis and limited treatment. Immune checkpoint inhibition, such as programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1), represents a major recent breakthrough in the treatment of diverse cancer including TNBC. Blocking PD-1 and PD-L1 interaction by antibodies has shown promising clinical effects. However, the response rate to PD-1 or PD-L1 antibody remains only at about 4.8%-26% in TNBC patients. A daunting challenge for improving efficacy of immunotherapy such as PD-1 antibody therapy is how to turn suppression CD8+ T cells to infiltrate tumor and kill tumor cells after the checkpoint- imposed brake is removed. Our extensive preliminary studies suggest that persistent STAT3 activation is critical for suppression of both innate and adaptive antitumor immunity. Ablating the Stat3 gene in T cells drastically induces CD8 TEFF cell tumor infiltration and antitumor effector functions, which mainly is through up-regulation of IFNγ and its inducible factors. However, the mechanism by which STAT3, a transcription factor, inhibits IFNγ remains unclear until we recently identified that STAT3 directly upregulates Carnitine palmitoyltransferase 1b (CPT1b) to promote fatty acid oxidation (FAO), which inhibits glycolysis and IFNγ expression in tumor CD8 T cells. However, to date clinically available STAT3 inhibitors are mainly JAK inhibitors, and JAKs are required for IFNγ triggered activation signaling, thus resulting in broader inhibition of targets that may be required for effector cell antitumor activities. In contrast, CD5 and PD-1 antibodies are receptor/pathway-limited and not expected to block JAK activation by other immunostimulatory molecules. Preliminary data indicate that CD5 and PD-1 are co- expressed on mouse breast cancer T and B cells, and both CD5 and PD-1 activate STAT3 and inhibit IFNγ which is necessary for therapeutic responses to PD-1/PD-L1 axis blockade. These extensive data led us to hypothesize that targeting CD5 in tumor-promoting CD5+ B cells and T cells enables PD-1 antibody therapy to effectively turn STAT3 dominance/IFNγ deficiency into IFNγ-rich anti-tumor immune activity in breast cancer mouse model. The central hypothesis will be tested in two aims: Aim 1. To assess the role of CD5/PD-1-STAT3 in regulating FAO/glycolysis metabolism and suppressing the CD8+ T cells capacity for anti-tumor function. Aim 2. To assess whether targeting CD5 on CD5+ B and T cells alters metabolism to enhance the anti-breast cancer effects of PD-1 blockade in mouse breast cancer model.