Tumor Microenvironment Remodeling in Triple Negative Breast Cancer Using Combination Therapy: One Size Does Not Fit All

Abstract

Breast cancer (BC) is the most diagnosed cancer and the leading cause of death in women worldwide. Triple negative breast cancer (TNBC) – defined by its lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) amplification – is an aggressive subtype of BC composing 10 – 20% of all BCs diagnosis. TNBC affects mostly younger patients of African American and Hispanic descent. Compared to other subtypes, TNBC patients are more likely to be overweight or obese, experience high rate of recurrence, distant metastasis, and poor overall survival.

Because of the lack of expression of targetable markers, the treatment landscape for TNBC patients is limited. Immunotherapy has shown great promises against other malignancies, such as melanoma, renal, lung and kidney cancers. The higher immunogenicity of TNBC; elevated load of non-synonymous mutations, tumor infiltrating lymphocytes (TILs) incidence, and PD-L1 expression has led to many clinical trials investigating the efficacy of immunotherapy in this subtype. Recently the FDA, approved the combination of immune checkpoint blockade (ICB), with docetaxel for the treatment of high-risk, early stage, locally advanced and metastatic TNBC. Yet, most patients do not benefit from these novel therapies.

In the studies described herein, we propose and define the mechanism by which two combinations therapies remodel the tumor microenvironment (TME) of TNBC to lead to a decrease in tumor progression, and an increase in survival. Both studies are conducted using two different syngeneic mice models of TNBC, to reflect the heterogeneity of the disease. In the first study, we describe the combination of docetaxel, with adenovirus IL-12 (adv.IL-12), and Anti-PD1. We show that the immunogenic cell death induced by docetaxel leads to the activation of dendritic cells (DCs), which in turn activate CD8 T-cells recruited to the TME by adv.IL-12, while anti-PD1 circumvent anergy. In the second study, we show how high fat diet promotes weight gain, tumor aggressiveness and metastasis. We then show that inducible nitric oxide (iNOS) inhibition, when combined with docetaxel leads to enhanced tumor growth inhibition, and less metastasis, especially in the context of obesity.