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Uncovering a novel function of BTLA on tumor-infiltrating CD8+ T cells
  1. Cara Haymaker1,
  2. Richard Wu1,
  3. Krit Ritthipichai1,
  4. Chantale Bernatchez1,
  5. Marie-Andree Forget1,
  6. Jie Qing Chen1,
  7. Hiu Liu2,
  8. Ena Wang2,
  9. Francesco Marincola2,3,
  10. Patrick Hwu1 and
  11. Laszlo Radvanyi1
  1. Aff1 grid.240145.60000000122914776MD Anderson Houston TX USA
  2. Aff2 grid.94365.3d0000000122975165National Institutes of Health Bethesda MD USA
  3. Aff3 Sidra Medical Research Hospital Doha Qatar

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Manipulation of T-cell co-inhibitory molecules, such as CTLA-4, PD-1, and BTLA has recently moved to the forefront of cancer immunotherapy. Although these molecules serve as inhibitors of T-cell activation, they are also biomarkers for activated T cells and may in fact have positive immune regulatory functions under certain circumstances. Recently, we demonstrated an unexpected positive association of CD8+ T cells expressing BTLA (B- and T- lymphocyte attentuator) with clinical response to adoptive T cell therapy in late-stage melanoma patients. We hypothesized that TIL may utilize the BTLA checkpoint differently and that key phenotypic and functional differences may exist between CD8+BTLA+ and CD8+BTLA- TIL subsets. In this study, we isolated and characterized BTLA+ and BTLA- CD8+ TIL from melanoma patients accrued in a Phase II clinical trial. We found that CD8+BTLA+ TIL had a superior proliferative response to IL-2 and a younger, more central memory T-cell behavior, such as secreting their own IL-2 after TCR stimulation. This younger and more robust memory phenotype was also associated with a longer persistence of T-cell clones in vivo in patients from the infused CD8+BTLA+ TIL subset. In contrast, CD8+BTLA- TIL were poorly proliferative, expressed killer-cell immunoglobulin-like receptors, and exhibited a gene expression signature of T cell deletion. As previously demonstrated, BTLA ligation with its cognate ligand herpes virus entry mediator (HVEM) resulted in decreased proliferation and inflammatory cytokine secretion. However, in a model of TIL activation induced cell death, we observed an enhanced survival of TIL co-cultured with HVEM+ target cells suggesting that BTLA ligation may also promote T-cell survival. Using a recombinant HVEM-Fc protein, we found that HVEM ligation of BTLA on CD8+ TIL activated the PI3K-Akt pathway resulting in the phosphorylation of Akt; this response was blocked using an anti-BTLA antibody. PI3K-Akt activation is most likely mediated by a unique GRB2-binding domain that exists in BTLA that can recruit PI3K via GRB2. As HVEM is expressed by many melanoma tumors and antigen-presenting cells these results suggest that HVEM ligation of BTLA on CD8+BTLA+ effector T-cells in the tumor microenvironment may play a dual role by reducing over-stimulation through the TCR and driving a PI3K-Akt-induced cell survival pathway. This survival signaling pathway may facilitate the longer persistence of the CD8+BTLA+ TIL subset in vivo in our patients. Our study has uncovered a novel role for BTLA both as a biomarker in TIL therapy and as a rheostat in perhaps fine tuning CD8+ T-cell responses rather than simply as a negative signaling pathway.