"The number of cancer patients is increasing and effective treatments are still limited. The identification of tumor associated antigens (TAA) has allowed for the stimulation of the immune system to recognize and destroy solid tumors. The most common strategy is to increase tumor specific cytotoxic CD8 T cell responses by vaccination of the patient with dendritic cells (DCs) pulsed with TAA peptides. Despite a great deal of efforts, these therapies have not proven efficient at complete rejection of tumors and metastases.While CD8 T cells have been at the center stage of anti-tumor immunotherapies, the role of CD4 T cells in tumor immunity has remained largely underappreciated, although some reports have shown that CD4 T cells alone are able to protect against transplanted tumors in mice. Given the multiplicity of CD4 T cell functions, finding ways to enhance productive anti-tumor CD4 T cell response is of tremendous therapeutic interest. This proposal aims at identifying strategies to manipulate the immune system for increasing the control of tumors and metastases. Emphasis will be put on the interactions between CD4 T cells, DCs, and Natural Killer (NK) cells. The project will address the following questions:(1) Are solid tumors overall poorly immunogenic for CD4 T cells?(2) What cells are relevant at the tumor and draining lymph node sites for the TAA uptake and presentation?(3) Can one enhance anti-tumor CD4 T cell responses by manipulating NK cell functions? If so, is the increase of CD4 T cell responses beneficial for the control of both the tumors and metastasis?To answer these questions, I will use molecular biology, cellular immunology and in situ imaging of the anti-tumor response by microscopy. Overall, I expect the results to lead to major advancements within the field of tumor immunology, and to possible translation to clinic."