Tissue Resident CD8 Memory T Cell Responses in Cancer and Autoimmunity

Abstract

Resident memory (T_RM) cells are a distinct tissue-localized T cell lineage that is crucial for protective immunity in peripheral tissues. While a great deal of effort has focused on defining their role in immunity to infections, studies now reveal T_RM cells as a vital component of the host immune response to cancer. Characterized by cell-surface molecules including CD103, CD69, and CD49a, T_RM-like tumor-infiltrating lymphocytes (TILs) can be found in a wide range of human cancers, where they portend improved prognosis. Recent studies in mouse tumor models have shown that T_RM cells are induced by cancer vaccines delivered in peripheral tissue sites, or by the depletion of regulatory T cells. Such tumor-specific T_RM cells are recognized as both necessary and sufficient for long-lived protection against tumors in peripheral tissue locations. T_RM responses against tumor/self-antigens can concurrently result in the development of pathogenic T_RM responses to self, with a growing number of autoimmune diseases and inflammatory pathologies being attributed to T_RM responses. This review will recount the path to discovering the importance of resident memory CD8 T cells as they pertain to cancer immunity. In addition to highlighting key studies that directly implicate T_RM cells in anti-tumor immunity, we will highlight earlier work that implicitly suggested their importance. Informed by studies in infectious disease models, and instructed by a clear role for T_RM cells in autoimmunity, we will discuss strategies for therapeutically promoting T_RM responses in settings where they don't naturally occur.

Keywords: CD103; TCM; TIL; TRM; biomarker; immunotherapy; melanoma; vitiligo.

Figure 1

Atlas of T_RM responses in peripheral tissues and tumors. CD8⁺ T_RM cells occupy a diverse array of tissues and tumors. For each tissue location, gray boxes indicate: (1) tumor types in which T_RM-like TILs have been identified (orange), (2) infections that give rise to T_RM responses (red), and (3) autoimmune or inflammatory conditions in which T_RM cells have been identified (green).

Figure 2

Skin resident-memory T cell responses to melanoma in the context of autoimmune vitiligo. Tumor-specific T_RM precursor populations are recruited from circulation into the skin by chemokine signals. Following entrance into the skin, these T cells kill melanocytes, develop into T_RM cells, and produce IFN-γ. Tumor-specific T_RM cells populate the dermis, epidermis, and hair follicles, where IL-15 is produced. CD103-dependent T_RM cells mediate the durable recall response to melanoma in the dermis.