Cancer immunotherapies have revolutionized the treatment of malignancies, but these therapeutics still face enormous challenges and limited efficacy in many patients. To overcome these limitations, improved strategies for CD8 T cell-targeted therapies will require increased understanding of how other immune players, particularly CD4 helper T cells, help in anti-tumor CD8 T cell immunity. CD4 T cells are thought to promote CD8 T cell responses by CD40-dependent ?licensing? of the antigen presenting cells (APCs) that prime CD8 T cells. It is now clear that CD8 T cells rely almost exclusively on conventional type 1 dendritic cells (cDC1) for priming against tumor and viral antigens. However, no study has directly identified the APC that primes the CD4 T cells responsible for licensing or clearly identified cDC1 as the target of CD4 licensing in vivo. The proposed research elucidates the cellular interactions required for priming anti-tumor CD4 T cells and mediating CD4 help for augmenting anti-tumor CD8 T cell responses. The overarching hypothesis is that in the setting of tumor-derived antigens, cDC1 function as an autonomous platform capable of priming both CD4 and CD8 T cells and orchestrating their crosstalk required for optimal anti-tumor immunity. This will be tested using novel in vivo genetic models that allow for selective manipulation of molecules in cDC1.
Aim 1 of this proposal investigates the hypothesis that cDC1 directly prime CD4 T cells against tumor-derived antigens.
This aim will examine the effect of antigen form during immunization on CD4 T cell priming in vivo and then compare anti-tumor CD4 T cells responses in models where MHC class II expression is selectively inactivated or induced on cDC1.
Aim 2 investigates the hypothesis that CD4 T cells indirectly provide necessary help for anti-tumor CD8 T cell priming and checkpoint blockade immunotherapy through CD40 signaling on cDC1.
This aim will characterize anti-tumor CD8 T cell responses and efficacy of checkpoint blockade immunotherapy in tumor-bearing models that genetically lack CD4 T cell help. It will also define the direct cellular interactions for CD40-dependent help. In the long term, the proposed work will increase mechanistic understanding of immune interactions against cancers, which may aid the development of more widely successful immunotherapies and treatments. This applicant is an MD-PhD candidate at an institution with a long history of supporting physician-scientists at all stages of their training and is working with a strongly committed mentoring team. The proposed training plan provides new conceptual and technical training, along with scientific, clinical, and career development activities that support a trajectory to become an independent physician-scientist focused on discovering mechanisms of cancer immunology that may be applied to develop novel strategies for therapies.
Cancer immunotherapies such as checkpoint blockade and adoptive T cell transfer therapy have revolutionized the treatment of malignancies, but these therapeutics still face enormous challenges and limited efficacy in many patients. To overcome these limitations, improved strategies for CD8 T cell-targeted therapies require an increased understanding of how other immune players, particularly CD4 helper T cells, can promote cytotoxic CD8 T cell responses against cancer neoantigens. The research proposed here seeks to determine the mechanisms by which anti-tumor CD4 T cells are primed and how they deliver help to augment anti-tumor CD8 T cell responses, which may provide insight for developing more effective and durable immunotherapies.
