Investigating The Distinct Role of Pd-L2 In Modulating Human T Cells Responses

<p><strong>INVESTIGATING THE DISTINCT ROLE OF PD-L2 IN MODULATING HUMAN T CELL RESPONSES</strong></p> <p>Anupallavi Srinivasamani, M.S.</p> <p>Advisory Professor: Michael A. Curran, Ph.D.</p> <p>Therapeutic blockade of the Programmed cell death-1 (PD-1) receptor and its ligand Programmed death ligand-1 (PD-L1) has revolutionized the treatment of multiple cancers and made durable tumor regression a possibility in the clinic. PD-1 blockade prolonged progression-free survival and overall survival with lesser high-grade toxicity in patients with advanced melanoma when compared to the other FDA-approved checkpoint blockade target, CTLA-4. Unlike CTLA-4, PD-1 is unique in its ability to regulate T cell functions in lymphoid tissues as well as in non-lymphoid tissues like the tumor microenvironment. The comparatively lower incidence of immune-related adverse events associated with PD-1 blockade and its wide-ranging immune-modulatory functions makes PD-1 signaling axis especially favorable for next-generation of combination therapies aimed at increasing the clinical efficacy of immune checkpoint blockade beyond the current 20% of patients who are expected to positively respond to PD-1/PD-L1 blockade. The current and future development of novel therapeutics targeting the PD-1 signaling axis should be rationally guided by a comprehensive understanding of the immunobiology underlying PD-1 signaling. However, the highest affinity ligand of PD-1, PD-L2 remains understudied and has yet to be directly interrogated for therapeutic potential. Recent reports have begun to reveal the relevance of PD-L2 in tumor immunology, however, critical gaps in our knowledge about the function of PD-L2, particularly in humans, limit efforts to rationally harness its potential clinical benefit. We therefore investigated the distinct function of PD-L2 in the PD-1/PD-L1/PD-L2 signaling axis in human T cells. To this end, we established an in vitro experimental system using human Jurkat T cells that allowed us to study the T cell regulatory functions of PD-1/PD-L1 and PD-1/PD-L2 complexes, exclusive of other protein-protein interactions on the surface of T cells. We resolved the contention over the nature of T cell regulation mediated by PD-L2 in preclinical murine models and conclusively showed that PD-L2 is solely a co-inhibitory ligand of human T cells. We also discovered the capacity of PD-L1 and PD-L2 to heterodimerize and studied the functional consequence of this interaction on T cell signaling. Despite binding to the same receptor, we demonstrated that PD-L1 and PD-L2 differentially engage PD-1 to induce a distinct inhibitory signaling cascade downstream of PD-1 in human T cells. We characterized the differences in the molecular mechanisms of PD-1/PD-L1 and PD-1/PD-L2 mediated inhibition of primary human T cells and elucidated the physiological impact of the differential signaling induced by PD-ligands through PD-1 on T cell function. Taken together, our work provides a more solid immunobiological foundation for clinical translation of PD-L2 and defines its non-redundant role in regulating T cell immunity in humans.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Srinivasamani, Anupallavi
• <p><a href="https://orcid.org/0000-0002-7799-1696">0000-0002-7799-1696</a></p>

Contributors dc:contributor

• Dr. Michael Curran
• Dr. Stephanie Watowich
• Dr. Pamela Wenzel

• Immune checkpoint inhibitors
• PD-L2
• T cell signaling
• PD-L1
• Immunotherapy
• Immunity
• Immunology and Infectious Disease
• Life Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1285

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2342