Multifaceted role of BTLA in the control of CD8+ T-cell fate after antigen encounter

Krit Ritthipichai, Cara L. Haymaker, Melisa Martinez, Andrew Aschenbrenner, Xiaohui Yi, Minying Zhang, Charuta Kale, Luis M. Vence, Jason Roszik, Yared Hailemichael, Willem W. Overwijk, Navin Varadarajan, Roza Nurieva, Laszlo G. Radvanyi, Patrick Hwu, Chantale Bernatchez

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, 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 costimulation. Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs. Results: CD8+BTLA- TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA- T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened "serial killing" capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response.

Original languageEnglish (US)
Pages (from-to)6151-6165
Number of pages15
JournalClinical Cancer Research
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility

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