2. Academic Validation
  3. Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function

Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function

  • J Immunother Cancer. 2021 Dec;9(12):e003339. doi: 10.1136/jitc-2021-003339.
Huaishan Wang  # 1,  Hui Chen  # 1,  Shujing Liu 1,  Jie Zhang 2,  Hezhe Lu 3,  Rajasekharan Somasundaram 4,  Robin Choi 4,  Gao Zhang 4 5,  Lingling Ou 1,  John Scholler 6,  Shifu Tian 1,  Liyun Dong 1,  Guo Yeye 1,  Lili Huang 1,  Thomas Connelly 4,  Ling Li 4,  Alexander Huang 7,  Tara C Mitchell 7,  Yi Fan 8,  Carl H June 1 6 9,  Gordon B Mills 10,  Wei Guo 11,  Meenhard Herlyn 4,  Xiaowei Xu 12
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 2 National Key Laboratory for Novel Software Technology, Nanjing University, Nanjing, China.
  • 3 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Science, Beijing, China.
  • 4 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
  • 5 Department of Neurosurgery, School of Medicine, Duke University, Durham, North Carolina, USA.
  • 6 Center for Cellular Immunotherapies, Perlman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 7 Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 8 Department of Radiation Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 9 Parker Institute for Cancer Immunotherapy, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 10 Cell, Developmental and Cancer Biology, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA.
  • 11 Department of Biology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 12 Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA xug@pennmedicine.upenn.edu.
  • # Contributed equally.
PMID: 34937742 DOI: 10.1136/jitc-2021-003339
Abstract

Background: Gamma delta (γδ) T cells are attractive effector cells for Cancer Immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive cell therapy. However, adoptive transfer of the expanded Vδ2 T cells has limited clinical efficacy.

Methods: We developed a costimulation method for expansion of Vδ2 T cells in PBMCs by activating γδ T-cell receptor (γδTCR) and Toll-like Receptor (TLR) 7/8 using isopentenyl pyrophosphate (IPP) and resiquimod, respectively, and tested the functional markers and antitumoral effects in vitro two-dimensional two-dimensional and three-dimensional spheroid models and in vivo models. Single-cell Sequencing dataset analysis and reverse-phase protein array were employed for mechanistic studies.

Results: We find that Vδ2 T cells expanded by IPP plus resiquimod showed significantly increased cytotoxicity to tumor cells with lower programmed cell death protein 1 (PD-1) expression than Vδ2 T cells expanded by IPP or ZOL. Mechanistically, the costimulation enhanced the activation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt)-the mammalian target of rapamycin (mTOR) pathway and the TLR7/8-MyD88 pathway. Resiquimod stimulated Vδ2 T-cell expansion in both antigen presenting cell dependent and independent manners. In addition, resiquimod decreased the number of adherent inhibitory antigen-presenting cells (APCs) and suppressed the inhibitory function of APCs by decreasing PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in these cells during in vitro Vδ2 T-cell expansion. Finally, we showed that human Vδ2 T cells can be expanded from PBMCs and spleen of humanized NSG mice using IPP plus resiquimod or ZOL, demonstrating that humanized mice are a promising preclinical model for studying human γδ T-cell development and function.

Conclusions: Vδ2 T cells expanded by IPP and resiquimod demonstrate improved anti-tumor function and have the potential to increase the efficacy of γδ T cell-based therapies.

Keywords

adjuvants; adoptive; costimulatory and inhibitory T-cell receptors; immunological; immunotherapy; melanoma.

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