PD-L1 and PD-L2 Regulation in triple negative breast cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer which is very aggressive, highly metastatic and often a recurrent type of disease. Conventional chemotherapy is currently the only, yet not always successful, systemic treatment option available for these patients. Due to their relatively high mutation rate, TNBC tumors are expected to be more immunogenic than other breast cancer subtypes. However, the ability of immune infiltrates to exert an anti-tumor immunological response is often suppressed by inhibitory molecules expressed by the tumor cells, such as PD-L1/PD-L2.
Although PD-L1-targeted therapy proved to be successful in treating several cancer types, not much is known about its regulation in TNBC. Here, we investigated the control of PD-L1/PD-L2 by pro-inflammatory mediators that prevail in TNBC and are connected to poor clinical outcome. Our results indicate that TNBC, but not luminal-A breast cancer cells (that have a better prognosis) express endogenous levels of PD-L1 and PD-L2. Approximately 50-70% of the cells express both molecules. Joint stimulation by two pro-inflammatory cytokines has led to significant up-regulation of PD-L1 and PD-L2 by TNBC cells, and the cytokines acted in a cooperative manner. To follow up on induction of NF-kB and STAT1 activation in the cells, using CRISPR-cas9 we found that the signals transmitted by p65 are channeled to STAT1 activation, which is the main regulator of PD-L1 and PD-L2 up-regulation.
Our findings indicate that pro-inflammatory signals induce the expression of immune checkpoints by TNBC cells, possibly potentiating their ability to escape anti-tumor immune activities. Our initial molecular analyses on the mechanisms up-regulating PD-L1/PD-L2 expression are now being followed by additional studies of the implications of these findings in TNBC tumor progression.