Using scRNAseq and scTCRseq, Han et al. showed that CD8+ T cells from matched tumor and distant vitiligo-affected skin, but not blood from patients with metastatic melanoma who responded well to immunotherapy comprised three distinct TRM subsets expressing high TCR signaling, high cytokine, or exhaustion signatures. Clonotypes shared in tumor, skin, and blood were of the highest frequency, preferentially expressed the high cytokine signature predictive of patient survival, and persisted as skin TRM and blood TEM cells for up to 9 years after tumor excision. Blood and particularly, skin T cells sustained memory against melanoma differentiation antigens.
Contributed by Paula Hochman
ABSTRACT: While T-cell responses to cancer immunotherapy have been avidly studied, long-lived memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8+ T-cell responses across tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident memory T (TRM) cells shared between tumors and distant vitiligo-affected skin. 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. Clonotypes that dispersed throughout tumor, skin and blood preferentially expressed an IFNG/TNF-high signature, which had a strong prognostic value for patients with melanoma. Remarkably, 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. These studies reveal that cancer survivors can maintain durable memory as functional, broadly distributed TRM and TEM compartments.