Chronic antigen in solid tumors drives a distinct program of T cell residence

Abstract

Abstract Resident-memory T cells (TRM) permanently reside in tissues, surveying the local environment for cognate antigen. Surrogate markers (e.g. CD69, CD103) and transcriptional programs from infection models are used as correlates of residency. Across numerous solid tumor types, TRM-like phenotypes have been identified and correlated with improved prognosis and responsiveness to immunotherapy. However, the migration properties of CD8+ tumor infiltrating lymphocytes (TILs) have not been well described. In this study, we employed parabiosis migration assays in a mouse model of breast cancer and demonstrated that both virus-specific bystander and tumor-specific CD8+ TILs can be resident. Canonical markers of TRM, including CD69, failed to discriminate between resident cells and recent migrants. However, the expression of markers associated with chronic T cell stimulation (PD-1, CD39, Tim-3) identified a population of resident, tumor-specific cells. We further observed that after tumor entry, Tcf-1+PD-1lo tumor-specific T cells progressively acquired the expression of inhibitory receptors, such as Tim-3, correlating with the phenotypes that represent tumor retention and residence. Thus, TRM exist within tumors, durable intratumoral residence was not informed by common markers associated with pathogen-specific TRM that have been described in healthy tissue, but tumor-specific T cells become resident upon tumor antigen recognition and the subsequent upregulation of CD39 and Tim-3. N.G. is a student in the Medical Scientist Training Program (MD/PhD) at the University of Minnesota and is currently supported through the National Cancer Institute (1F30CA253992-01) with past support from the Dr. Warren J. Warwick and Henrietta Holm Warwick Fellowship. Research supported by the National Cancer Institute (1R01CA238439-01A1, D.M.).