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 IFN¿ and its inducible factors.
However, the mechanism by which STAT3, a transcription factor, inhibits IFN¿ remains unclear
until we recently identified that STAT3 directly upregulates Carnitine palmitoyltransferase 1b
(CPT1b) to promote fatty acid oxidation (FAO), which inhibits glycolysis and IFN¿ expression in
tumor CD8 T cells. However, to date clinically available STAT3 inhibitors are mainly JAK
inhibitors, and JAKs are required for IFN¿ 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 IFN¿ 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/IFN¿ deficiency into
IFN¿-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.