Abstract
Resident memory (TRM) 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 TRM cells as a vital component of the host immune response to cancer. Characterized by cell-surface molecules including CD103, CD69, and CD49a, TRM-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 TRM cells are induced by cancer vaccines delivered in peripheral tissue sites, or by the depletion of regulatory T cells. Such tumor-specific TRM cells are recognized as both necessary and sufficient for long-lived protection against tumors in peripheral tissue locations. TRM responses against tumor/self-antigens can concurrently result in the development of pathogenic TRM responses to self, with a growing number of autoimmune diseases and inflammatory pathologies being attributed to TRM 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 TRM 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 TRM cells in autoimmunity, we will discuss strategies for therapeutically promoting TRM responses in settings where they don't naturally occur.
Highlights
Cancer can be considered a disease of immune dysfunction, with a failure of immune recognition leading to the outgrowth of malignant cells as tumors [1]
Employing therapeutic depletion of regulatory T cells to break tolerance to melanoma differentiation antigens, followed by surgery to curatively excise residual B16 primary tumors, we identified the formation of tumor/self Ag-specific CD8 T cells in the skin with a CD44hi CD62Llow CD103+ CD69+ cutaneous leukocyte antigen (CLA)+ tissue-resident memory (TRM) phenotype (Figure 2) [111]
This study extended a link between tumor immunity and autoimmunity formed by our earlier work that autoimmunity against normal melanocytes maintains lymphoid memory T cell responses against melanoma/melanocyte shared antigens [112, 113]
Summary
Cancer can be considered a disease of immune dysfunction, with a failure of immune recognition leading to the outgrowth of malignant cells as tumors [1]. While innate immune cells are important for early tumor immune surveillance, T cells are fundamentally recognized for their crucial role in the antigen-specific recognition and elimination of malignantly transformed cells [2]. In a growing number of cases, CD8 T cells have been shown to mediate the regression of large bulky tumors, resulting in durable longterm disease remissions [5]. The persistence of such responses is fundamentally thought to be based on the ability of T cells to act as potent effectors and, subsequently, generate longlived memory [6]. As the field of cancer immunotherapy advances rapidly, it is crucial to understand how the dissemination and maintenance of tumor-specific T cells can be optimally achieved
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