Oral Presentation Eradicate Cancer 2020

Increased and co-localized CD4+FOXP3+ and CD8+ T cells is a strong independent prognostic indicator in gastric cancer (69573)

Minyu Wang 1 2 3 , Yu-Kuan Huang 1 2 , Joe Kong 2 , Yu Sun 2 , Heloise Halse 3 , Daniela Tantalo 3 , Han Xian Aw Yeang 3 , Le Ying 4 , Feng Yan 5 , Natasha Di Costanzo 1 , Ian R. Gorden 6 , Catherine Mitchell 7 , Rita A. Busuttile 1 , Paul J. Neeson 3 , Alex Boussioutas 1
  1. Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic, Australia
  3. Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  4. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic, Australia
  5. Australian Centre for Blood Diseases, Monash University, Melbourne, Vic, Australia
  6. Statistical consulting center, School of Mathematics and Statistics, The University of Melbourne, Melbourne, Vic, Australia
  7. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia

Background: For patients with gastric cancer (GC), immune context data has had an inconsistent association with clinical outcome.

Methods: To address this issue, we used high dimension data analysis to characterize primary treatment-naïve GC tumor immune context, in a clinically comprehensive cohort of gastric cancer patients. We assessed the association of immune cell type densities and their spatial relationships with patients’ outcomes. We then correlated these data with paired transcriptome  to define a GC immune signature and profiled the immune cells from the peripheral blood to assess the association of immune cell subsets presented in the blood with lymphocytes infiltration into the tumor using mass cytrometry.

Results: Interestingly, increased GC patient survival correlated with increased CD4+FOXP3+ T cells infiltrated in the tumor core. Using a novel algorithm (Intercellular Spatial Analysis Tool, ISAT)1 we measured the median intercellular nearest distance between immune cell subsets and tumor cells. In the GC tumor core of patients with a good clinical outcome, the ISAT analysis showed increased CD4+FOXP3+ T cells were closely associated with CD8+ T cells, and not tumor cells. Furthermore, increased tumor core CD8+ and CD4+FOXP3+ T cells (CD8highCD4FOXP3high) was an independent predictor for prolonged GC patient survival, regardless of established clinical variables. It further revealed CD8highCD4FOXP3high GC was strongly associated with an increased interferon-gamma response, antigen presentation, dendritic cell differentiation and PDL1 up-regulation in the local tumors, as well as enrichment of Tbet+ CD4+ T cells and central memory CD4+ T cells circulating in the peripheral blood. In contrast, the CD8LowCD4FOXP3Low exhibited a high frequency of PDL1+ dendritic cells in the peripheral blood and low immune infiltrates in the tumor.

Conclusion: In conclusion, using a combination of gene expression, multiplex immunohistochemistry and mass cytometry, our study showed a new biomarker for good clinical outcome in GC patients, and also points to opportunities for novel immunotherapy strategies.

  1. Wang, M., Sun, Y. & Huang, Y. K. ISAT: extract cell density and nearest distance based on ‘PerkinElmer InForm’ software output. https://cran.rproject.org/web/packages/ISAT/index.html (2018).