Tomasz Zal, Ph.D.

Our laboratory is interested in tissue regulation of immunity, which we investigate by combining various immunological and genetic techniques with dynamic visualization such as by intravital multiphoton, confocal, FRET and super-resolution fluorescence microscopy.

The immune system can recognize cancerous cells in vivo, and tumor antigen-recognizing cytotoxic lymphocytes can exterminate such cells in vitro, but the in vivo anti-tumor immune responses are subdued by the hostile tumor microenvironment. Exactly how lymphocytes are affected by the tumor microenvironment is of primary interest for the design and optimization of anti-tumor immunotherapies. To better understand the spatiotemporal regulation of immune cells inside tumors, we use intravital microscopy and a variety of agents, including nanomaterials in various tumor models in mice. By this approach, we can visualize and quantify the dynamics of specific cell populations and signaling pathways at a single cell- and subcellular-resolution in the context of tissue in vivo. We find in lung metastases that the recruitment and activity of tumor-infiltrating lymphocytes critically depends on tumor-associated CD11c + dendritic cells (DCs) and that these DCs can both promote and downregulate anti-tumor immune responses. Thus on the one hand, tumor-associated DCs can probe the cytoplasm of cancer cells, thereby initiating tumor antigen cross-presentation, but on the other hand this complex cell population recruits and interacts with the FoxP3+ Treg cells - an immune-suppressory T cell subpopulation. Currently, our goal is to understand how the interactions between tumor cells, DCs, Treg cells and other tumor-infiltrating lymphocytes are regulated in vivo with the hope that these interactions can be targeted for anti-tumor immunotherapy.

T cells recognize antigens through the T cell antigen receptor (TCR), whose composition divides all T cells into the alpha/beta and gamma/delta lineages. Unlike alpha/beta T cells which circulate through lymphoid organs, gamma/delta T cells reside primarily in environment-exposed bodily epithelia, such as in the intestine, reproductive organs, lungs, and in mice, the epidermis, where they are involved in tissue surveillance and homeostatic functions. Both alpha/beta and gamma/delta T cell lineages can become cytotoxic toward tumors and without them cancers progress rapidly. It is well established that most alpha/beta TCRs recognize MHC-associated non-self peptides, which can arise due to infection or mutations, such as cancer-driving mutations, but the biological role of gamma/delta TCRs is less clear. Using intravital and in situ microscopy in mice, we discovered that the epidermal gamma/delta T cells use their canonical Vg5 TCR to engage in a steady-state activatory interaction with the healthy epidermis, resulting in the formation of synapse-like phosphotyrosine-rich assemblies located on projections (PALPs) near the apical barrier-forming squamous keratinocyte tight junctions, including in germ-free mice. Our results indicate that intraepithelial gamma/delta TCRs may recognize distinctly localized epithelial self-ligands. We hope to leverage the intravital visualization approach to understand how this and other receptor-ligand interactions contribute to the anti-tumor and homeostatic functionalities of gamma/delta T cells.

Degree-Granting Education

Postgraduate Training