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).

Available for download on Friday, June 02, 2023

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