Devalaraja et al., Cell, 2020 Dang et. al., Cell Reports, 2021 Alam et. al., Cell Reports, 2020
We study how tissue microenvironment influence the development and function of mononuclear phagocytes (MP cells) of the innate immune system, which comprises of monocytes, dendritic cells (DC), and macrophages. Dendritic cells excel at antigen presentation to induce adaptive immune responses while tissue-macrophages are versatile cells with roles in innate immunity and tissue homeostasis. Many distinct phenotypic and functional subsets of these cells have been described. Each tissue harbors its own unique repertoire of DC and macrophage subsets, which undergoes significant changes during pathological conditions such as inflammation, infection, tumor, etc. Circulating monocytes can infiltrate tissue and undergo differentiation into either DC or macrophage, but factors that control this decision process is not fully understood. Macrophages can also develop from embryonic precursors, independent of monocytes. Likewise, DCs also develop from bone-marrow derived precursors independent of monocytes. Therefore, MP cells are phenotypically, functionally, and developmentally heterogeneous. We are interested in understanding molecular mechanisms that control this heterogeneity in the steady state as well as in pathological conditions such as cancer.
The evolution of multiple immune evasion pathways in tumors underscores the impact of immune system on cancer. The ‘tumor-immunity cycle’ begins with the processing of tumor-associated proteins by dendritic cells (DC), which initiate a T-cell response in draining lymph nodes, followed by the trafficking of these anti-tumor T cells into the tumor to mediate tumor lysis (Figure) Tumors can block one or more steps of this cycle to evade immune responses. The therapeutic potential of targeting such immune-evasion pathways is highlighted by the clinical success of immune checkpoint inhibitors that alleviates T cell suppression in cancer. However, tumor-reactive T cells are not generated in most solid tumors, which limit the utility of immune checkpoint inhibitors. A major reason for this failure to generate anti-tumor T cells is the paucity and dysfunction of DCs in tumor microenvironment. While DCs are rare inside tumors, a closely related cell type, macrophages (MACs), are abundant. In contrast to DCs, tumor-associated macrophages (TAMs) are usually immunosuppressive and promote tumor progression. Both DCs and TAMs can originate from monocytes. A major interest in our laboratory is to understand why monocytes preferentially differentiate into immunosuppressive TAMs but not immunostimulatory DCs in solid tumors. The overarching goal of targeting these cells for cancer immunotherapy. In our approach, we integrate data from genetically engineered mouse models, patient-derived materials, basic molecular biology, and high dimensional immune and genomic profiling.