PKHB1, a thrombospondin-1 peptide mimic, induces anti-tumor effect through immunogenic cell death induction in breast cancer cells

Abstract

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women worldwide. Recent advances in the field of immuno-oncology demonstrate the beneficial immunostimulatory effects of the induction of immunogenic cell death (ICD). ICD increases tumor infiltration by T cells and is associated with improved prognosis in patients affected by triple negative breast cancer (TNBC) with residual disease. The aim of this study was to evaluate the antitumoral effect of PKHB1, a thrombospondin-1 peptide mimic, against breast cancer cells, and the immunogenicity of the cell death induced by PKHB1 in vitro, ex vivo, and in vivo. Our results showed that PKHB1 induces mitochondrial alterations, ROS production, intracellular Ca 2+ accumulation, as well calcium-dependent cell death in breast cancer cells, including triple negative subtypes. PKHB1 has antitumor effect in vivo leading to a reduction of tumor volume and weight and promotes intratumoral CD8 + T cell infiltration. Furthermore, in vitro, PKHB1 induces calreticulin (CALR), HSP70, and HSP90 exposure and release of ATP and HMGB1. Additionally, the killed cells obtained after treatment with PKHB1 (PKHB1-KC) induced dendritic cell maturation, and T cell antitumor responses, ex vivo. Moreover, PKHB1-KC in vivo were able to induce an antitumor response against breast cancer cells in a prophylactic application, whereas in a therapeutic setting, PKHB1-KC induced tumor regression; both applications induced a long-term antitumor response. Altogether our data shows that PKHB1, a thrombospondin-1 peptide mimic, has in vivo antitumor effect and induce immune system activation through immunogenic cell death induction in breast cancer cells.

PKHB1 peptide induces antiviral effects through induction of immunogenic cell death in herpes simplex keratitis

“…In a follow-up study, which immune cell is the one that plays a key role in the increased IFN-γ secretion will be further explored. PKHB1 peptide has been shown to induce ICD in various oncological diseases such as breast cancer and leukemia (Uscanga-Palomeque et al, 2019;Calvillo-Rodríguez et al, 2022). The low immunogenicity of infected cells is a significant obstacle to anti-infective therapy.…”

“…These DAMPs recruit APCs to ICD sites and stimulate the uptake, processing, and presentation of dead cell-associated antigens, resulting in the adaptive immune response (Tesniere et al, 2008;Krysko et al, 2012;Bezu et al, 2015). Calvillo-Rodríguez et al (2022) recently designed a peptide named PKHB1 based on the structure-activity relationship of the C-terminal binding domain (CBD) of platelet response protein-1 (TSP-1). The peptide sequence is kRFYVVMWKk with terminal D-lysines (Denèfle et al, 2019;Leclair et al, 2020).…”

“… Calvillo-Rodríguez et al (2022) recently designed a peptide named PKHB1 based on the structure-activity relationship of the C-terminal binding domain (CBD) of platelet response protein-1 (TSP-1). The peptide sequence is kRFYVVMWKk with terminal D-lysines ( Denèfle et al, 2019 ; Leclair et al, 2020 ).…”

Research progress in inducing immunogenic cell death of tumor cells

“…In addition to the inducers mentioned above, several novel chemical agents have been recently shown to induce ICD responses in tumor cells in basic experiments. These new ICD inducers include resveratrol ( 118 ), non-steroidal anti-inflammatory drugs ( 86 ), PKHB1 ( 88 ), and belantamab mafodotin ( 80 ).…”

“…Moreover, its action on tumor cells induces alterations in mitochondrial structure, Ca 2+ accumulation, and calcium-dependent cell death. In addition, it increased the number of cytotoxic T lymphocytes, DC activation and maturation, and decreased immunosuppressive cells such as Treg cells, promoting tumor cell death ( 87 , 88 ).…”