Dendritic cell orchestration of the anti-tumor T cell response:

       Dendritic cells (DCs) represent the most potent cell type capable of sensing pathogens and priming antigen-specific T cell responses. To fulfill this specialized function, DCs exhibit a set of characteristics conserved across mammals, including elevated expression of certain pattern-recognition receptors, upregulation of antigen-presentation machinery and costimulatory molecules upon activation, the ability to carry antigen intracellularly from the periphery to tissue-draining lymph nodes, and even robustness against direct viral infection. However, DCs are also necessary for induction of tolerance against self-antigens. While DCs are both necessary for the induction of anti-tumor T cell responses and present in tumor lesions, we believe that tumors are able to take advantage of this latter, tolerogenic, DC function in order to avoid T-cell mediated destruction.

       Recently, we used CITEseq profiling in a Kras-G12D/Tp53-null murine model of lung adenocarcinoma and human NSCLC lesions to identify a DC state expressing both maturation and immunoregulatory molecules (mregDC), which could be modulated by stimulation with or blocking of IL4 signaling. We are therefore interested in understanding how IL4 signaling may arise in the tumor microenvironment, as well as its role in human disease. Accordingly, we plan to open a phase I study of anti-IL4Ra (dupixent; regeneron) for treating NSCLC, and are planning focused study around the DC response. To identify other immunomodulatory pathways, we are taking advantage of the pro-code CRISPR-screening technology developed in collaboration with the Brian Brown lab to probe the phenotypic effect of knocking out an array of genes implicated in mregDC function.