The Role of the Endocannabinoid System in the Treatment of Triple-Negative Breast Cancer with Immunotherapy

Triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancer cases and has the worst prognosis among the subtypes of this disease. Immunotherapy in combination with chemotherapy is a new treatment used in early and advanced stages of the disease. Some patients have primary resistance, but most develop secondary resistance during treatment. Autoimmune side effects are also a major problem. The challenge is therefore to find new and better biomarkers that will allow a more selective choice of patients who will benefit from such a therapy. In most preclinical in vitro and in vivo studies on TNBC, the antitumor activity of cannabinoids has been established. Cannabinoids are known to have an immunosuppressive effect, primarily through CB2 modulation. In addition, research has confirmed that medical cannabis can negatively impact treatment outcomes (OS) in metastatic cancer patients treated with immune checkpoint inhibitors (ICIs). As more and more cancer patients are exposed to various cannabinoids during treatment, research in this area is needed. Selective antagonists/inverse agonists of the cannabinoid receptor type 2 (CB2) could represent a new approach to increase the sensitivity or to overcome resistance of TNBC to ICI therapy.

The aim of this research project is to determine the effects of the endogenous cannabinoid 2-AG and the selective antagonist/inverse agonist CB2 in combination with ICI and chemotherapy in a mouse model of TNBC and to evaluate the prognostic and predictive significance of cannabinoid receptor (CBR) expression and serum 2-AG levels in treatment with immunochemotherapy, which has not been studied before.