RESEARCH OVERVIEW:
Antitumor CD8 T cells rely upon several environmental cues to productively eliminate malignant cells, including within the tumor microenvironment and tumor draining lymph nodes. The overall goal of the Brown Lab is to mechanistically define signals within the tumor microenvironment and lymphatics to recruit and engage functional antitumor T cell responses.
1. Pattern Recognition Receptors (PRRs) recognize diverse pathogen (viruses, bacteria, fungi) features to induce innate immune inflammation. The innate arm of the immune system rapidly detects pathogens on the basis of ‘non-self’ features (e.g., double-stranded RNA) using PRRs and coordinate an anti-pathogen response that encompasses cytotoxic mediators, initiation of cell death, and inflammation that shapes and eventual adaptive immune response (Figure 1).
Figure 1. PRR cellular locations, specificities and downstream signaling. Yellow indicates PRRs, blue indicates signaling mediators, and red indicates transcription factors that mediate transcription of inflammatory genes. Arrows indicate signaling/modifications that transduce signals to tell the cell to induce inflammation. Pathogen associated features that activate PRRs are depicted in italicized red text. Upon recognizing a pathogen feature, PRRs induce signaling cascades that lead to the production of inflammatory mediators (including cytokines and type I IFNs), that lead to recruitment of additional immune cells and engage anti-pathogen immune responses.
2. PRRs control recognition and elimination of cancer cells by the immune system. PRR-induced inflammation is critical for a productive antitumor immune response (Figure 2).
Figure 2. 1) Cancer cells routinely die due to stress, chemo/radiation, nutrient deprivation, hypoxia, etc; leading to the release of tumor antigens. 2) Migrating antigen presenting cells take up antigen in the tumor microenvironment to be processed and presented to T cells. PRRs potentiate this step by increasing antigen presentation, increasing antigen uptake, and recruiting additional migratory DCs into tumors. 3) Within the draining lymph node or other secondary lymphoid organ, tumor antigen loaded DCs present antigen to T cells, leading to their activation. PRR signaling induces the expression of co-stimulatory signals on DCs to potentiate T cell priming/activation. 4) T cells traffic to the site of the tumor by surveying PRR dependent endothelial ligand expression and chemokine signals, and 5) infiltrate the tumor tissue. 6) T cells recognize cognate tumor antigen presented on tumor cells; PRRs facilitate this process by inducing inflammation that causes induction of antigen presentation machinery in cancer cells. 7) T cells kill cancer cells expressing their cognate antigen via granzymes and perforin, FAS ligand, and secretion of cytotoxic cytokines; PRRs induce inflammation that enhances antitumor T cell function and cytotoxicity. Adapted from Chen and Mellman. Immunity 2013.
3. Triggering antiviral inflammation can revive antitumor immune responses, i.e. ‘in situ vaccination’. Our focus is to leverage the role of PRRs in the cancer immunity cycle (Figure 2) to mediate cancer immunotherapy (Figure 3). However, optimal routes to harness the innate immune system for cancer immunotherapy have yet to be clinically realized, molecular mechanisms by which the innate immune system controls antitumor immunity in gliomas are crudely defined, and determinants of in situ vaccination success remain unexplored.
Figure 3. Intratumor administration of viruses and virus-like features engage PRRs in tumor associated cells, including macrophages which constitute up to 50% of the tumor mass in gliomas. The resultant innate inflammation can enhance tumor antigen presentation and delivery of activating signals to antitumor T cells. This in turn leads to generation of functional antitumor T cells that eliminate cancer cells and/or may prevent recurrence.
