Mechanisms of T Cell Dysfunction in Chronic Lymphocytic Leukemia and Viral Associated Carcinoma

Abstract

T cell exhaustion compromises anti-tumor immunity, and a sustained elevation of coinhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). CD8+ T cells play an essential role against tumors, but mechanisms associated with their exhaustion in various cancers are diverse and yet to be elucidated. This research study evaluates the mechanism(s) associated with CD8+ T cell phenotype and function in CLL and immunotherapy-related immune signatures in HPV-associated (Human Papilloma Virus) carcinoma. First, I examined the expression of different co-inhibitory receptors in CD8+ T cells obtained from peripheral blood/bone marrow of CLL patients by flow cytometry. I found CD160 as the most dominant co-inhibitory receptor in these patients. Its expression was associated with an exhausted T cell phenotype, and CD160+CD8+ T cells were highly antigen-experienced T cells. Furthermore, we proposed chronic stimulation, CD160-containing EVs, and elevated IL-16 levels as mechanisms linked to the expansion of CD160-expressing CD8+T cells in CLL. Moreover, I found a significant decline in CD26 expressing CD8+ T cells in CLL compared to healthy subjects. My findings demonstrated that CD26high cells were enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161, TV7.2, and IL-18R. Also, I observed that CD26high cells have a rich chemokine receptor profile (e.g., CCR5 and CCR6), profound cytokine (TNF-, IFN-, and IL-2), and cytolytic molecules (Granzyme B, K, and perforin) expression upon stimulation. Overall, my results demonstrate that CD26+ T cells possess a natural polyfunctionality to traffic, exhibit effector functions, and resist exhaustion. In turn, Galectin-9 (Gal-9) and the inflammatory milieu (IL-18, IL-12, and IL-15) in CLL patients contribute to the depletion of CD26high T cells. Hence, depletion of MAIT cells may predispose CLL patients to immune dysfunction and susceptibility to infections. Furthermore, I conducted bulk RNA sequencing analysis of peripheral immune cells to gain insight into immune checkpoint blockade therapy in advanced HPV-associated carcinoma patients. I discovered that the immune cell signature in responders to immunotherapy is entirely different from non-responders at the baseline and following treatment. The genes and pathways related to myeloid immune responses were more prominent in the non-responding group, which supports their suppressive role in this group. In agreement, non-responders had higher levels of IL-8 and IL-18 at the baseline than responders. In contrast, responders had higher CD8+ T cells at the endpoint. These observations highlight potential mechanisms of T cell exhaustion in hematologic malignancies such as CLL versus solid tumors. My studies have provided a novel insight into the underlying mechanism(s) of immune dysfunction with potential clinical implications for precision medicine.