PROJECT SUMMARY / ABSTRACT
Triple negative breast cancer (TNBC) is a highly aggressive cancer that has a poor prognosis and limited
treatment due to the high propensity for metastatic progression and absence of specific targeted treatments.
Although the immune checkpoint inhibition represents a breakthrough in the treatment of diverse cancers, 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 PD1 antibody therapy is how to turn suppressed
CD8+ T cells to activated cells after the checkpoint-imposed brake is removed. Our lab and others have shown
that persistent STAT3 activation is critical for suppression of antitumor immunity. Our recent studies
demonstrated that PD-1-ligation on CD8+ T cells activates STAT3 to upregulate CPT1B/fatty acid oxidation (FAO)
while inhibiting glycolysis/IFN¿ and CD8+ T cells antitumor effector. However, the compromised antitumor effects
of CD8 TEFF cells are heavily impacted by suppressive immune cells including CD5+ B cells. We reported that
cancer-promoting role of B cells depends on CD5-induced STAT3 activation. In addition to CD5+ B cells, in our
pilot study performed under 1R21CA241283, we found that CD5 and PD-1 are co-expressed highly on mouse
breast cancer T cells, which increased STAT3 activity in tumor infiltrating CD8+ T cells to suppress T cell anti-
tumor function through regulating FAO/glycolysis. Furthermore, we demonstrated that targeting CD5 on T and B
cells enhanced the anti-tumor effect of PD-1 blockade in PyMT mouse model of breast cancer. However, how to
turn up glycolysis and stimulate IFN¿ expression in TEFF cells to improve the efficacy of antitumor immune therapy
in breast cancer patients remains elusive. Guided by our preliminary data, we hypothesize that (i) CD5/PD-1-
induced STAT3 activation in T cells inhibits the antitumor immune responses of CD8+ T cells and counteracts
PD-1 antibody therapy by promoting FAO and inhibiting glycolysis in breast cancer patients. (ii) effectively
inhibiting STAT3/FAO in tumor-associated T cells, which can be achieved by blocking CD5, will “fuel” tumor
infiltrating CD8+ T cells to meaningfully improve the antitumor efficacy of PD-1 blockade. We will accomplish our
overall objective by pursuing the following specific aims: Aim 1: To assess whether CD5/PD-1-STAT3 axis-
regulated FAO and glycolysis metabolism in T cells from patient breast tumor samples is associated with CD8+
TEFF cell exhaustion and failure to benefit from PD-1-directed therapy. Aim 2: To assess the antitumor effect and
mechanisms through which CD5 and PD-1 antibodies alters T cell metabolism to enhance CD8 TEFF activity in
patient-derived tumor organoids (PDTOs) and mice bearing patient-derived xenografts (PDXs) with autologous
T cells or human immune system. Together, these studies will provide new mechanistic insights and key
preclinical evidence of therapeutic resistance to PD-1 blockade, and will identify novel therapeutic strategy for
overcoming resistance to PD-1 blockade and extend the benefits of PD-1 blockade therapy for TNBC patients.