Effect of PD-L1 blockade along with autophagy inhibition on the anti-tumor immune response

Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease. In Europe, every year, almost 60,000 new cases are diagnosed and approximately 16,000 people die from this disease. In Luxembourg, the estimated incidence of melanoma was 14.2 per 100,000 in 2012. Patients with unresectable or metastatic melanoma have a poor prognosis with an average overall survival of approximately one year for stage IIIc or IV of the disease.The approval of monoclonal antibodies (mAbs) targeting immune checkpoint inhibitors such as PD-1/PD-L1 has dramatically changed the treatment of advanced melanoma in recent years. Although these mAbs have demonstrated an impressive clinical responses and positive impact on overall survival in advanced melanoma patients, the related toxicity and the development of resistance in some patients are emerging challenges to overcome in order to improve melanoma mmunotherapy. There is increasing evidence that a combination therapy aiming to target resistance mechanisms and immunotherapy could provide long-lasting responses in a broader spectrum of patients. The present project is designed to evaluate the effectiveness of immune checkpoint inhibitors in combination with targeting autophagy-dependent resistance mechanism, activated under hypoxia,using a well-defined syngeneic melanoma mouse model. The rationale for the use of such combination relies on the fact that hypoxia-dependent activation of autophagy in the tumor microenvironment is the key factor involved in the impairment of the anti-tumor immune response by upregulating the expression of several immune checkpoints. The ultimate objective of this project is to provide the proof-of concept to conduct clinical trials for the use of immune checkpoint inhibitors in combination with drugs inhibiting autophagy as innovative therapeutic approaches for the treatment of melanoma. This project fully complies with the objectives of National Cancer Plan whose Cancer Immunology was defined as one of the major research axes and a priority domain.