Characterizing the migration and therapeutic potential of CD8 tumor-infiltrating lymphocytes

Abstract

Beginning in the 19th century, immunologists slowly uncovered the mechanisms ofcancer immunosurveillance, ultimately identifying thymic-dependent “T” lymphocytes (T cells), and not antibodies, as the primary mediators of cancer cell elimination and control. T cell surveillance is performed by diverse subsets. After antigen encounter, T cells differentiate, adopting many phenotypic fates. In settings of acute infection, T cells diversify into ‘effector’ and long-lived ‘memory’ states. While some memory T cells circulate throughout the body, others remain resident, patrolling tissues locally. The migration and function of memory T cells has been well studied, providing a systemic view of immune surveillance for microbial pathogens. In settings of chronic antigen, such as cancer, antigen-specific T cells diverge from the memory program, existing along a spectrum of differentiation and exhibiting restrained functional capabilities. While the early stages of cancer immunosurveillance mirror immune responses to microbial pathogens, the T cell surveillance of progressive malignant tumors is poorly understood. Many studies describe the heterogeneity of tumor-infiltrating T cells (TILs). Generally, the density of CD8+ TILs correlates with improved prognosis, but the density of CD8+ TILs with resident-memory (TRM) phenotypes better predicts patient outcomes and responsiveness to immunotherapies. These TRM-like cells may directly control tumor growth, but their migration properties have not been directly studied, leaving their direct function unknown. Importantly, newer data shows that many CD8+ TILs are bystanders, specific for microbial pathogens, not tumors. Reactivation of these bystander T cells with cognate peptide can orchestrate potent anti-tumor immune responses. In this thesis, I study the migration properties of tumor-specific and virus-specific CD8+ T cell subsets. Distinct resident populations of CD8+ TILs exist, differing based on the presence or absence of chronic antigen. Resident CD8+ TILs do not recapitulate the resident T cell programs of healthy tissues. I also investigated the anti-tumor immune mechanisms initiated by antiviral CD8+ TILs reactivation. Cytokine production and innate immune mechanisms were the predominant source of tumor killing. Taken together, T cell immunosurveillance is characterized by the coexistence of T cell subsets that represent lineages associated with chronic antigen exposure and memory T cells, which possess potent therapeutic potential (e.g. TRM).