Poster Presentation Melbourne Immunotherapy Network Winter Symposium 2021

Selective expansion of CCR6-Vdelta2+Vgamma9+ T-cells following treatment with phosphoantigens or bisphosphonates in pigtail macaques (Macaca nemestrina) (#102)

Isaac M Barber-Axthelm 1 , Kathleen M Wragg 1 , Anne M Gibbon 2 , Stephen J Kent 1 3 4 , Jennifer A Juno 1
  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
  2. Monash Animal Research Platform, Monash University, Clayton, Victoria, Australia
  3. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Parkville, Victoria, Australia
  4. Melbourne Sexual Health Centre and Infectious Disease Department, Alfred Health, Monash University Central Clinical School, Melbourne, Victoria, Australia

Introduction: Phosphoantigen reactive gamma-delta T-cells, characterised by their expression of a Vdelta2 TCR, have garnered significant interest as immunotherapies against cancers and infectious diseases. These cells can be readily expanded pharmacologically and are capable of mediating a wide variety of immune functions, including pro-inflammatory cytokine production and lysis of target cells. Despite promising results in preclinical studies, the clinical efficacy Vdelta2+ T-cell immunotherapies has been limited. Improving Vdelta2+ T-cell immunotherapies will require treatment protocol refinements to optimise expansion and activation of these cells.

 

Methods: The aim of this study was to investigate the impact of different antigenic stimuli and routes of administration on Vdelta2+Vgamma9+ T-cell expansion in nonhuman primates. Pigtail macaques were treated with intravenous (IV) or intratracheal (IT) zoledronate, HMB-PP (IV and IT), or IPP (IT), along with IL-2 to stimulate in vivo Vdelta2+Vgamma9+ T-cell expansion. Vdelta2+Vgamma9+ T-cell frequencies and phenotypes were evaluated in blood and tissues sites (lymph nodes, bronchoalveolar lavage fluid [BAL], and rectal mucosa) over time, and compared to baseline samples.

 

Results: Vdelta2+Vgamma9+ T-cells readily expanded in the peripheral blood of macaques treated with systemic zoledronate or HMB-PP, and in the BAL fluid of macaques treated with IV and IT antigens. Vdelta2+Vgamma9+ T-cell frequencies were consistently low in the lymph nodes and rectal mucosa, with no significant changes in cell frequencies in any of the treatment groups. Expanded Vdelta2+Vgamma9+ T-cells in the blood were predominately CCR6-, which was not observed in Vdelta2+Vgamma9+ T-cells in the BAL.

 

Conclusion: Vdelta2+Vgamma9+ T-cells readily expand in the blood and airway mucosa of pigtail macaques following treatment with phosphoantigens or bisphosphonates. Systemic phosphoantigen and bisphosphonate mediated expansion with IL-2 preferentially expands CCR6-Vdelta2+Vgamma9+ T-cells in the blood. This work has implications for improving Vdelta2+ T-cell immunotherapies against both infectious and neoplastic diseases.