Immunotherapy on triple negative breast cancer

The purpose of this research is to identify Triple Negative Breast Cancer (TNBC) therapeutic agents. Recent statistics showed that 20% of the breast cancer patients in the U.S. have been diagnosed with subtype TNBC (92736). Unfortunately, no promising therapeutic targets have been identified for its treatment. Our laboratory has previously shown that there is a correlation between high levels of MYC oncogene expression and poor prognosis. Pharmaceutical inhibition of MYC, a transcription factor that is thought to drive tumor development, is technically difficult, which excludes it as a direct therapeutic target. This study focuses on an immunotherapeutic approach to treat or control TNBC tumor progression. In this study, we focus on the immune inhibitory checkpoint blockade of PD-L1, a promising anti-cancer therapeutic technique with the potential for more durable and objective response, higher efficacy, lower toxicity and lower risk of recurrence. This immunotherapeutic approach has recently been used in humans for treating various types of cancer, including melanoma, non-small cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC). The rationale of this approach is based on the ability of the immune system to attack tumor cells. Considering that tumor-infiltrating lymphocytes are one of the known clinical characteristics of TNBC, the inability of the immune system to fight against cancer is due to an immune resistance mechanism involved in cancer survival. The tumor-cancer cell interaction initiates an immunosuppressive pathway in infiltrating lymphocytes, resulting in the inhibition of cytokine release and the attenuation of tumor specific T-cell activity. This effect is most likely mediated by immune inhibitory receptors expressed on TILs. Thus, targeting this immune inhibitory checkpoint is assumed to restore the patient’s immune cell function and fight against breast tumors. Programmed cell Death protein 1 (PD1) and its two best-characterized ligands, PD-L1 and PD-L2 comprise one crucial immune checkpoint pathway. The PD-L1 is expressed in 50% of human solid tumors including melanoma, breast, lung, colon, ovarian, and likely accounts for immune tolerance. Moreover, recent studies show that this protein is highly expressed in TNBC. Despite these findings, the role of PD-L1 in TNBC immunosuppression and its corresponding molecular pathway are not yet clear. This research aimed to study the effect of PD1-PD-L mediated immunosuppression on TNBC tumor progression as well as recurrence. We also aimed to study the effect of secondary mutations on tumor progression, immune response, and immune inhibitory molecules expression. In this study we unveiled the importance of PD-L1 expression on the myeloid cells for the effectiveness of anti-PD-L1 immune checkpoint blockade approach. We found that despite the lack of PD-L1 expression on MYC-driven tumor cells, anti PD-L1 treatment delayed tumor recurrence and primary tumor progression. We have shown that myeloid subpopulations, namely monocytes and PMNs, expressed PD-L1 and it is suggested that they exhaust tumor-specific CD8+ T cells through the PD1immune inhibitory checkpoint pathway. Hence, the blockade of PD-L1 most likely restored the antitumor lymphocytes’ function and caused the observed delay in tumor progression and recurrence. We also found that line A tumor recruited neutrophils significantly more than line B and this population, after CD4+ T cells, constituted the majority of the tumorinfiltrated immune cells in line A. Further analysis is required to ensure this difference in the neutrophil population is not due to the effect of secondary mutation(s). We also found that PVR, another immune inhibitory ligand, was expressed significantly on the tumor cells as well as tumor-infiltrating myeloid cells and we postulate that PVR may be another candidate to be targeted alone or in combination with anti-PD-L1 to increase the effectiveness of an immunotherapy-based regiment for treatment of TNBC.