Date of Award
2022
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Mary Jo Turk
Abstract
While T-cell responses to cancer immunotherapy have been avidly studied,
long-lived memory has been poorly characterized. Of melanoma patients who
receive immunotherapy, long-term survivors are frequently found to develop
melanoma-associated vitiligo. Our prior work showed in a preclinical model that
vitiligo skin sustained a long-lived CD8+ resident memory T cell (TRM) population,
playing key roles in perpetuating anti-tumor immunity. However, the characteristics
and longevity of these memory T cells in melanoma survivors have not been defined.
In the present studies, we probed both the CD8+ and CD4+ T cell responses,
focusing on memory T cell responses in a cohort of metastatic melanoma survivors
with exceptional responses to immunotherapy. Single-cell RNA sequencing
revealed heterogenous CD8+ and CD4+ TRM subsets shared between tumors and
distant vitiligo-affected skin with distinct prognostic significance. Paired T-cell
receptor sequencing further identified clonotypes in tumors that co-existed as TRM
in skin and as effector memory T (TEM) cells in blood. CD8+ T cell clonotypes that
dispersed throughout tumor, skin and blood preferentially expressed an IFNG/TNFhigh
signature, which had a strong prognostic value for patients with melanoma. An
unbiased core TRM gene signature capturing the abundance of overall TRM
regardless of the CD4+ and CD8+ different differentiation lineages was proved to
be a better predictor for the overall survival of metastatic melanoma patients than a
core circulating T cell (TCIRC) gene signature. Remarkably, the CD8+ T cell
clonotypes from tumors were found in patient skin and blood up to 9 years later, with
skin maintaining the most focused tumor-associated clonal repertoire.
This work established that cancer survivors can maintain durable memory as
functional, broadly distributed TRM and TEM compartments. Moving forward, it will be
necessary to determine the tissue microenvironment factors that are required for the
induction and persistence of tumor reactive TRM populations in patients for better
immunotherapies.
Original Citation
Han, J. et al. Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy. Nat Cancer 2, 300-311, doi:10.1038/s43018-021-00180-1 (2021).
Recommended Citation
Han, Jichang, "Profiling durable anti-tumor memory T cell responses in long-term melanoma survivors" (2022). Dartmouth College Ph.D Dissertations. 87.
https://digitalcommons.dartmouth.edu/dissertations/87
