A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer that lacks an estrogen receptor, the progesterone receptor and the human epidermal growth factor receptor 2 (HER2), making it unsuitable for hormonal- or HER2-based therapy. TNBC is known for its higher relapse rate, poorer prognosis and higher rate of metastasis compared to non-TNBC because although patients initially respond to chemotherapy that kills cancer cells through a form of programmed cell death called apoptosis, they later develop chemoresistance and stop responding to the treatment, accounting for one fourth of all breast cancer deaths. In this study, we report a novel compound, TPH104, that elicits a unique, non-apoptotic cell death in TNBC cells. Upon treatment with TPH104, TNBC cells swell and burst, releasing immunogenic markers that alert and activate the immune system to further recognize and attack the neighboring breast cancer cells. ABSTRACT: Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing the stimulatory capacity of dendritic cells (DCs), with an IC(50) value of 140 nM. TPH104 (5 µM) significantly increased ATP levels in the supernatant and mobilized intracellular calreticulin to the plasma membrane in MDA-MB-231 cells, compared to cells incubated with the vehicle. Incubating MDA-MB-231 cells for 12 h with TPH104 (1–5 µM) significantly increased TNF-α mRNA levels. The supernatants of dying MDAMB-231 cells incubated with TPH104 increased mouse bone marrow-derived DC maturation, the expression of MHC-II and CD86 and the mRNA expression of TNF-α, IL-6 and IL-12. Overall, these results indicate that TPH104 induces immunogenic cell death in TNBC cells, in part, by activating DCs.