Mechanistic and Functional Characterization of B and T Lymphocyte Attenuator (Btla) In Cd8 Tumor Infiltrating Lymphocytes

<p>This dissertation project focused on understanding the functional role of BTLA on CD8⁺ Tumor Infiltrating Lymphocytes (TIL) from metastatic melanoma patients. Clinical trials of adoptive T-cell therapy (ACT) using autologous <em>ex vivo </em>expanded TIL have demonstrated the great potential of this immunotherapy with an overall clinical response rate 40-50% for stage IV metastatic melanoma patients. We have investigated a number of biomarkers in both the infused TIL and the tumor microenvironment for their association with clinical response. Surprisingly, a subset of CD8⁺TIL expressing the co-inhibitory molecule BTLA (B-and-T lymphocyte attenuator) was highly associated with clinical response, while expression of other co-inhibitory molecules such as PD-1, TIM-3, and Lag3 did not associate with response. BTLA is expressed by T cells, B cells, and NK cells and serves as a T cell differentiation maker whereby high expression of BTLA associates with less differentiated T cell phenotype. While the suppressive function of the ITIM and ITSM motifs of BTLA are well described, the Grb2 motif’s function remains understudied.</p> <p>In this study, we sought to determine the functional characteristics of the CD8⁺BTLA⁺TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation. We have uncovered a survival advantages of the BTLA⁺ subset that allows for serial killing of target tumor cells, which may explain our previous correlation between this subset and response to TIL ACT. BTLA-HVEM interaction during T cell activation led to the specific activation of SRC kinase. In addition, our results unveiled a role for the BTLA-associated Grb2-binding motif in T cell proliferation and IL-2 production following TCR engagement that was independent of the inhibitory function of ITIM/ITSM motifs.</p> <p>Overall, our study first unveil the dual role of BTLA as both a co-stimulatory and co-inhibitory molecule. The integration of the positive and negative signals transduced by BTLA promotes IL-2 secretion while reducing certain effector function of T cell. Altogether, the combination of both BTLA signaling and inherent attributes of less differentiated T cells could promote T cell survival, persistence, and anti-tumor function.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2016

Author dc:creator

• ritthipichai, krit

Contributors dc:contributor

• Patrick Hwu
• Chantale Bernatchez
• Roza Nurieva

• Immunotherapy
• T cell therapy
• TIL
• BTLA
• Melanoma
• CD8
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/685

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1729