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

• Author / Creator

  Bozorgmehr, Najmeh

• 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.

• Subjects / Keywords

  • T cell exhaustion
  • Chronic Lymphocytic Leukemia
  • HPV associated carcinoma

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-hqd2-ah26

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.