Defining the barriers to immune surveillance in solid tumors

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Project Summary The prognosis for pancreatic cancer is extremely poor, and it can surely benefit from better clinical interventions. Immunotherapy has been ineffective in achieving significant clinical responses in pancreatic ductal adenocarcinomas (PDAC), despite its success as a treatment module for various other cancers. This failure of immunotherapy is likely due to the stunted anti-tumor T cell response observed in clinical and pre-clinical studies. Very little is known about how antigen-directed anti-tumor immune surveillance becomes undermined over PDAC progression. The long term aim of the F99 phase project is to address some major questions in the field, namely—Does neoantigenicity even trigger host immunity and influence tumor outcome in pancreatic cancer, and what are the key barriers to T cell activity in the periphery and local microenvironment of PDAC? The proposed studies will exploit a novel mouse model of PDAC (KPC-OG) to spatiotemporally control expression of an engineered neoantigen (OVA) in spontaneously developing pancreatic cancer using doxycycline control. Using this robust clinically-relevant model, the proposal will address important questions regarding immune surveillance in PDAC; these would specifically include (a) addressing the proposed ‘immune privilege’ of pancreata by studying the effect of antigenicity on PDAC progression and host immune response, (b) analyzing activation and expansion of OVA-specific T cells in PDAC-associated lymphatic system to assess antigen-priming defects, and (c) studying the dynamic interaction between OVA-specific T cells and tumor dendritic cells to identify trafficking and antigen-presentation dysfunctions in the PDAC stroma. The outcomes from this proposal will be highly impactful in the field due to its dissection of PDAC immune escape. Indeed, this work will be highly informative in the clinic for developing better interventions for PDAC and similar solid tumors. This proposal channels the PI’s long-term scientific interest of visualizing interactions between host immunity and developing tumors to better understand mechanisms of immune escape in solid tumors. Experiments planned as part of this proposal will bridge several techniques in tumor immunology, and skills gained in this phase will be advantageous for the PI’s intended career in oncoimmunology. The planned K00 postdoctoral phase will involve studying the mechanisms by which tumor-draining lymph nodes influence systemic immunity against solid tumors, specifically determining how these lymphatics get co-opted in immune escape mechanisms. The postdoctoral training is envisioned to build upon the PI’s existing tumor-immunology skillset, but involve more training in cutting-edge quantitative imaging of immune cell interactions in tumor lymph nodes and lymphatic vessels. Indeed, proposed training across the F99 & K00 phases tie into the PI’s long-term goal to examine the broader mechanisms by which lymphangiogenic dysfunctions regulate tumor progression, and his research objective to develop novel immunotherapy targeting this lymphatic network.