Date of Award
Summer 8-17-2023
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Mary Jo Turk
Second Advisor
Edward J. Usherwood
Third Advisor
Patricia A. Pioli
Abstract
Although there has been extensive research on T-cell responses to cancer immunotherapy, the understanding of long-lasting memory in visceral organs remains less well understood. Among these, a population of Trm cells was discovered that reside durably within tumor draining lymph nodes (TDLN) and plays a crucial role in protecting against invading melanoma cells, uncovering a new role for Trm cells at critical metastatic sites. However, little is known about the molecular mechanisms promoting Trm establishment in tissues where cancer can develop and metastasize. Here, employing longitudinal T cell receptor (TCR)-lineage-tracing and single-cell transcriptomics, we find that TDLN contain Teff cells expressing not only canonical residency markers, but also stemness and survival characteristics prior to Trm differentiation. Clonal tracing revealed that although Teff cells seeded growing tumors equally well, they remained Trm poised in the TDLN, and differentiated into Trm cells without the need for retrograde tissue migration. Notably, generation of widely distributed Trm cells, especially in lymph nodes, was promoted by type 1 interferon sensing by their Trm precursors. Furthermore, we discovered that CXCR3 deficient CD8+ T cells were unable to infiltrate tumors, incapable of seeding and persisting in the skin and TDLN. This was in contrast to their equivalent priming in the TDLN. Finally, we examined the trafficking patterns of tumor Ag-specific CD8+ T and discovered that they migrated from skin to TDLN only during primary tumor growth in an S1P dependent manner. However, tumor re-challenge resulted in skin Trm reactivation and secondary Trm response in lymph nodes. iii Overall, we identify key molecular determinants, specific to the microenvironment of TDLN, that influence the ongoing anti-tumor response and foster the formation of multipotent Trm cells. Our findings also suggest that retrograde Trm responses from peripheral tissue reservoirs may enhance systemic anti-tumor immunity. These findings may inform strategies for optimizing CD8+ Trm responses at sites of metastatic cancer.
Recommended Citation
khatwani, nikhil, "Molecular mechanisms governing the generation of tissue resident memory CD8 T cells in the setting of cancer" (2023). Dartmouth College Ph.D Dissertations. 216.
https://digitalcommons.dartmouth.edu/dissertations/216