Abstract
Triple-negative breast cancer (TNBC) is characterized by the lack of clinically significant levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Owing to the aggressive nature and the emergence of resistance to chemotherapeutic drugs, patients with TNBC have a worse prognosis than other subtypes of breast cancer. Currently, immunotherapy using checkpoint blockade has been shown to produce unprecedented rates of long-lasting responses in patients with a variety of cancers. Although breast tumors, in general, are not highly immunogenic, TNBC has a higher level of lymphocyte infiltration, suggesting that TNBC patients may be more responsive to immunotherapy. The identification/characterization of immune checkpoint molecules, i.e., programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PDL1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), represents a major advancement in the field of cancer immunotherapy. These molecules function to suppress signals downstream of T cell receptor (TCR) activation, leading to elimination of cytotoxic T lymphocytes (CTLs) and suppression of anti-tumor immunity. For TNBC, which has not seen substantial advances in clinical management for decades, immune checkpoint inhibition offers the opportunity of durable response and potential long-term benefit. In clinical investigations, immune checkpoint inhibition has yielded promising results in patients with early-stage as well as advanced TNBC. This review summarizes the recent development of immune checkpoint inhibition in TNBC, focusing on humanized antibodies targeting the PD1/PDL1 and the CTLA4 pathways.
Highlights
Triple-negative breast cancer (TNBC), accounting for about 10–20% of all breast cancer cases, is the most aggressive and fatal subtype of breast cancer [1, 2]
In a phase I/II trial (NCT02489448), stage I–III TNBC patients were evaluated in terms of whether they produced a higher pathological complete response (pCR) with adding durvalumab to nab-paclitaxel weekly and with dose-dense doxorubicin and cyclophosphamide for 4 cycles compared with chemotherapy alone
While immune checkpoint inhibition through the PD1/programmed cell death ligand 1 (PDL1) axis and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) may still not be satisfactory in TNBC, other molecules such as T cell immunoglobulin and mucin-3 (TIM3), lymphocyte activating gene 3 (LAG3), and TIGIT are investigated in some studies [51, 52]
Summary
Immunotherapy using checkpoint blockade has been shown to produce unprecedented rates of long-lasting responses in patients with a variety of cancers. The identification/characterization of immune checkpoint molecules, i.e., programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PDL1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), represents a major advancement in the field of cancer immunotherapy. These molecules function to suppress signals downstream of T cell receptor (TCR) activation, leading to elimination of cytotoxic T lymphocytes (CTLs) and suppression of anti-tumor immunity.
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