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
5544 - Evaluation of a radiomic signature of CD8 cells in patients treated with immunotherapy-radiotherapy in three clinical trials.
Presenter: Roger Sun
Session: Poster Display session 3
Resources:
Abstract
1117 - Biomarkers predictive of overall survival in advanced cancer patients treated with a peptide-based cancer vaccine.
Presenter: Shigetaka Suekane
Session: Poster Display session 3
Resources:
Abstract
1922 - Expression of PD-L1 in plasma exosomes of NSCLC patients and its associations with PD-L1 expression of corresponding tumor tissues
Presenter: Shaorong Yu
Session: Poster Display session 3
Resources:
Abstract
5495 - Patient’s perspective on digital biomarkers in advanced urologic malignancies
Presenter: Severin Rodler
Session: Poster Display session 3
Resources:
Abstract
3166 - A comprehensive Pan-cancer study of FGFR Aberrations in Chinese cancer patients
Presenter: Yang Gao
Session: Poster Display session 3
Resources:
Abstract
3277 - A Systemic Inflammation Response Index (SIRI) correlates with survival and could be a Predictive Factor for mFOLFIRINOX in Metastatic Pancreatic Cancer (PC)
Presenter: Vilma Pacheco-Barcia
Session: Poster Display session 3
Resources:
Abstract
2680 - Circulating biomarkers and risk of immune-related adverse events (irAEs) in patients (pts) with advanced Non-small cell lung cancer (aNSCLC) and metastatic melanoma (mMel)
Presenter: Alberto Pavan
Session: Poster Display session 3
Resources:
Abstract
4066 - Breast cancer in young women of Kazakh population depending on germline mutations: results of next-generation sequencing
Presenter: Dilyara Kaidarova
Session: Poster Display session 3
Resources:
Abstract
5514 - Discovery of an ImmunoTranscriptomics signature in blood for early colorectal cancer detection
Presenter: Paolo Angelino
Session: Poster Display session 3
Resources:
Abstract
1595 - Serum Netrin-1 as a Biomarker for Colorectal Cancer Detection
Presenter: Jinzhou Zhu
Session: Poster Display session 3
Resources:
Abstract