Characterization of Differentiation and Prognostic Biomarkers On Cd8+ Tumor-Infiltrating Lymphocytes In Metastatic Melanoma

<p>CD8⁺ cytotoxic T lymphocytes (CTL) frequently infiltrate tumors, yet most melanoma patients fail to undergo tumor regression. We studied the differentiation of the CD8⁺ tumor-infiltrating lymphocytes (TIL) from 44 metastatic melanoma patients using known T-cell differentiation markers. We also compared CD8⁺ TIL against the T cells from matched melanoma patients’ peripheral blood. We discovered a novel subset of CD8⁺ TIL co-expressing early-differentiation markers, CD27, CD28, and a late/senescent CTL differentiation marker, CD57. This CD8⁺CD57⁺ TIL expressed a cytolytic enzyme, granzyme B (GB), yet did not express another cytolytic pore-forming molecule, perforin (Perf). In contrast, the CD8⁺CD57⁺ T cells in the periphery were CD27^-CD28^-, and GB^Hi and Perf^Hi. We found this TIL subset was not senescent and could be induced to proliferate and differentiate into CD27^-CD57⁺, perforin^Hi, mature CTL. This further differentiation was arrested by TGF-β1, an immunosuppressive cytokine known to be produced by many different kinds of tumors. Therefore, we have identified a novel subset of incompletely differentiated CD8⁺ TIL that resembled those found in patients with uncontrolled chronic viral infections.</p> <p>In a related study, we explored prognostic biomarkers in metastatic melanoma patients treated in a Phase II Adoptive Cell Therapy (ACT) trial, in which autologous TIL were expanded <em>ex vivo</em> with IL-2 and infused into lymphodepleted patients. We unexpectedly found a significant positive clinical association with the infused CD8⁺ TIL expressing B- and T- lymphocyte attentuator (BTLA), an inhibitory T-cell receptor. We found that CD8⁺BTLA⁺ TIL had a superior proliferative response to IL-2, and were more capable of autocrine IL-2 production in response to TCR stimulation compared to the CD8⁺BTLA^- TIL. The CD8⁺BTLA⁺ TIL were less differentiated and resembled the incompletely differentiated CD8⁺ TIL described above. In contrast, CD8⁺BTLA^- TIL were poorly proliferative, expressed CD45RA and killer-cell immunoglobulin-like receptors (KIRs), and exhibited a gene expression signature of T cell deletion. Surprisingly, ligation of BTLA by its cognate receptor, HVEM, enhanced the survival of CD8⁺BTLA⁺ TIL by activating Akt/PKB. Our studies provide a comprehensive characterization of CD8⁺ TIL differentiation in melanoma, and revealed BTLA as a novel T-cell differentiation marker along with its role in promoting T cell survival.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2013

Author dc:creator

• Wu, Richard C

Contributors dc:contributor

• Laszlo G. Radvanyi, Ph.D.
• Russell Broaddus, M.D., Ph.D.
• Dapeng Zhou, M.D., Ph.D.

• Adoptive T-cell Therapy
• CD8+ effector memory
• Cytotoxic T Lymphocytes
• Tumor-infiltrating lymphocytes
• Melanoma
• B and T Lymphocyte Attenuator
• T-cell survival/persistence
• Biological Phenomena, Cell Phenomena, and Immunity
• Cancer Biology
• Immunity
• Medical Immunology
• Medicine and Health Sciences
• Neoplasms
• Oncology
• Skin and Connective Tissue Diseases
• Therapeutics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/366

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1401