Adoptive T cell therapy using tumor-infiltrating lymphocytes (TIL) expanded ex vivo with high-dose IL-2 is a promising approach for the treatment of metastatic melanoma. Recently, our lab demonstrated the importance of CD8+ T cells expressing B and T lymphocyte attentuator (BTLA) with a positive clinical response. This suggests that functional differences may exist between CD8+BTLA+ and CD8+BTLA- cells resulting in the differential therapeutic potency of TIL in treated patients. Here, we isolated BTLA+ and BTLA- CD8+ TIL from metastatic melanoma patients accrued in a Phase II clinical trial at MD Anderson and performed functional assays measuring proliferation, apoptosis, cytokine production, and CTL activity as well as differences in global gene expression profiles between the subsets using microarray analysis. Overall, BTLA appears to be a new and powerful biomarker distinguishing a less differentiated, more highly active and polyfunctional CD8+ T cell subset with high responsiveness to IL-2. As BTLA ligation by its binding partner HVEM (which is expressed on melanoma cells) results in a decreased proliferative responsiveness to anti-CD3 stimulation, paradoxically, BTLA signaling however may still serve as a negative co-inhibitory molecule. Our results also underscore that increased expression of T cell co-inhibitory molecules may not be necessarily markers of “exhaustion”, but markers of more highly-activated, responsive T cells susceptible to negative regulation.
- Copyright © 2013 by The American Association of Immunologists, Inc.