Checkpoint Inhibition in Triple-Negative Breast Cancer
Triple-negative breast cancer is a highly heterogeneous breast cancer subtype that has been defined by the lack of a target. It has been subdivided into 6 different subgroups based on its molecular heterogeneity that include basal-like, mesenchymal-like, mesenchymal stem-like, luminal androgen receptor expression, immunomodulatory and an unstable type.43 For years it was thought that this disease is resistant to immunotherapy, however recent studies have shown evidence of significant immune infiltration of TILs (tumor-infiltrating lymphocytes) in a subset of patients with triple-negative breast cancer. Triple-negative breast cancer seems to have a high expression of PDL1 and harbors a strong infiltration by immune cells in the actual tumor bed. TILs seem to have both a prognostic as well as predictive power, with high numbers correlating with better outcome and better response to therapy. Elevated TIL scores were proven to correlate with increased pathological complete response to neoadjuvant chemotherapy.44–47 This proves that the immune system plays a pivotal role in this subgroup of patients.
Based on that, efforts were generated to prime the immune system to elicit an immune response capable of fighting off those cancer cells. Immune checkpoint blockade exploited this mechanism at its best through targeting the PD1/PDL1 pathway. PD1 (programmed cell death-1) receptor is a cell surface membrane protein, member of the B7 family of checkpoints that is expressed on the surface of activated T cells. PD1 is activated by its ligands PD-L1 and PD-L2 that are commonly expressed on the surface of dendritic cells or macrophages as well as on tumor cells. When activated, the PD1/PDL1 pathway leads to the suppression of the T-cell-mediated immune response, which normally can minimize states of chronic inflammation and help control autoimmune diseases.
Unfortunately, Tumor cells can exploit this pathway to evade the immune detection system or what is called the cancer immunity cycle. Tumor cells overexpress PDL1 and trigger the PD1/PDL1 pathway, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment that leads to the unopposed proliferation of cancer cells.
Anti-PD-1 antibodies (like Pembrolizumab and Nivolumab) and anti-PDL-L1 antibodies (like Atezolizumab and Durvalumab) have been developed and are currently being investigated. Those monoclonal antibodies aim to restore the immune system by disrupting the PD1/PDL1 interaction.48 However, it remains to be seen whether PD1 or PDL1 blockade is better.
A similar pathway being investigated is targeting the Cytotoxic T lymphocyte-associated protein 4 (CTLA-4). CTLA4 is a T cell inhibitory receptor that is expressed on activated CD4+ and CD8+ T cells that specifically overexpress CD25 and foxp3. CTLA4 is upregulated by activation of T cell receptor and cytokines such as Il-12 and IFN gamma, which usually forms a negative feedback to, activated T cells leading to a physiologic break of the immune response. CTLA-4 was initially implicated in cancer when in vivo it was demonstrated that blockade of the inhibitory effects of CTLA-4 can release the brake and potentiate the immune response against tumor cells leading to tumor regression in mouse models of sarcoma and colon adenocarcinoma. Anti CTLA-4 drugs are currently being investigated. Ipilimumab has already been approved in melanoma and is currently being investigated in breast cancer.17 Tremelimumab another anti-CTLA4 is also being investigated.
Other targets that are being investigated for potential checkpoint inhibition include the BTLA, VISTA, TIM3, LAG3, and CD47 proteins but are very early in development.49,50 We will review next the active and completed clinical trials exploring those drugs specifically in triple-negative breast cancer.
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