Abstract 3733
Background
Immune check point inhibitor therapy has shown efficacy in Triple-negative breast cancer (TNBC), highlighting the immune-responsive microenvironment of TNBC. Recently, anti-cancer therapeutics have been shown to induce immunogenic cell death (ICD). MEK/ERK cascade mediates T cell receptor signaling and involves in immune response. MEK inhibitor cobimetinib is approved for advanced melanoma and is studied in several clinical trials including breast cancer. Here, we aimed to explore the anti-tumor and immunomodulatory effects of cobimetinib in TNBC.
Methods
Damage-associated molecular patterns (DAMPs), cell-surface translocation of calreticulin (CRT), extracellular release of ATP, and increase in high-mobility group box protein B1 (HMGB1) release from dying tumor cells, were examined by immunoblotting and flow cytometric analysis. The pan-caspase inhibitor z-VAD-FMK was used to validate cobimetinib-induced signaling. The immunocompetent and immunodeficient mice were conducted to investigate the efficacy of cobimetinib.
Results
Cobimetinib significantly induced cell apoptosis and DAMPs in TNBC cells (human MDA-MB-231, MDA-MB-468, and murine 4T1 cells). Cobimetinib downregulated p-ERK and activated caspase-8, in association with increased DAMPs such as HMGB1 and CRT. Cobimetinib-induced CRT was attenuated by ectopic ERK expression. Moreover, cobimetinib-induced cell apoptosis and increased CRT expressions were restored by the pan-caspase inhibitor. The anti-tumor activity of cobimetinib was superior in immunocompetent than in immunodeficient mice. DAMPs and caspase-8 cascade were upregulated in cobimetinib-treated 4T1 xenografts. Interestingly, the immunomodulation of cobimetinib in 4T1-bearing mice were different from that in non-tumor bearing immunocompetent mice. Importantly, cobimetinib-treated 4T1-bearing immunocompetent mice exhibited increased total number of CD8+ T cells, effector CD4+ T cells, regulatory T cells and reduced the number of myeloid-derived suppressor cells, compared to vehicle-treated mice.
Conclusions
Our findings suggest that the MEK inhibitor cobimetinib acts as an ICD-inducer and exerts immunomodulatory effects in TNBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Chun-Yu Liu.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5071 - Expression of estrogen receptor and programmed cell death-ligand 1 can be complementary prognostic factors in HPV-positive oropharyngeal squamous cell carcinoma
Presenter: Soohyeon Kwon
Session: Poster Display session 3
Resources:
Abstract
5306 - Real-world data of clinicopathologic characteristics of young oropharyngeal cancer patients.
Presenter: Maria Nieva
Session: Poster Display session 3
Resources:
Abstract
3407 - The clinical significance and biological mechanisms of miR-499a in high-tobacco exposed head and neck squamous cell carcinoma
Presenter: Shiqi Gong
Session: Poster Display session 3
Resources:
Abstract
3310 - Liquid biopsy for mutational profiling of locoregional recurrent and/or metastatic squamous cell carcinoma of the head and neck
Presenter: Rachel Galot
Session: Poster Display session 3
Resources:
Abstract
2362 - Blood-based testing of mutations in patients with Head and neck squamous cell carcinoma (HNSCC) using highly sensitive SafeSEQ technology
Presenter: Florentia Fostira
Session: Poster Display session 3
Resources:
Abstract
4533 - The head and neck Lung Immune Prognostic Index (HN-LIPI): a prognostic Score for Immune Checkpoint Inhibitors (ICI) in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN) patients.
Presenter: Ruth Gabriela Herrera Gomez
Session: Poster Display session 3
Resources:
Abstract
5262 - Immune-related adverse events (irAEs) and outcome in recurrent/metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) patients (pts) treated by immune-checkpoints inhibitors (ICI)
Presenter: Neus Baste Rotllan
Session: Poster Display session 3
Resources:
Abstract
3725 - Intratumoral and peripheral exploratory biomarker analysis in patients with locoregional, recurrent head and neck squamous cell carcinoma (rHNSCC) treated with RM-1929 photoimmunotherapy
Presenter: Jack Bui
Session: Poster Display session 3
Resources:
Abstract
2533 - A nomogram based prognostic score to predict overall survival (OS) in recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with immune checkpoint inhibitors (ICI).
Presenter: Luay Mousa
Session: Poster Display session 3
Resources:
Abstract
2929 - Changes of the Commensal Microbiome during Treatment are Associated with Clinical Response in the Nasopharyngeal Carcinoma Patients
Presenter: Tingting Huang
Session: Poster Display session 3
Resources:
Abstract