Poster Presentation 18th International Symposium on Dendritic Cells 2026

Leveraging DC and T cell crosstalk to improve cancer immunotherapy (#239)

Cheok Weng Chan 1 2 , Junyun Lai 1 2 , Jesse D Armitage 1 2 3 4 , Katherine M Audsley 1 2 , Yu-Kuan (Tony) Huang 1 2 , Emily B Derrick 1 2 , Laura S Carstensen 1 2 , Christina M Scheffler 1 2 , Matt E Jones 5 , Kevin Sek 1 2 , Nicola Principe 6 , Joelle S Kim 1 2 , Imran G House 1 2 , Amanda XY Chen 1 2 , Kah Min Yap 1 2 , Jim Middelburg 1 2 , Isabelle Munoz 1 2 , Dat Nguyen 1 2 , Junming Tong 1 2 , Thang X Hoang 1 2 , Kirsten L Todd 1 2 , Maximilien Evrard 7 , Jonathan Chee 6 , Laura K Mackay 7 , Alistair RR Forrest 5 , Ian A Parish 1 2 , Anthony Bosco 8 9 , Jason Waithman 3 , Paul A Beavis 1 2 , Phillip K Darcy 1 2
  1. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
  3. School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
  4. The Kids Research Institute Australia, The University of Western Australia, Perth, WA, Australia
  5. Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WA, Australia
  6. Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, WA, Australia
  7. Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia
  8. Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA
  9. Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ, USA

Immune checkpoint blockade (ICB) therapies enhance anti-tumor immunity by reinvigorating tumor-specific T cell responses, yet only a fraction of patients derives durable benefit. Thus, a major focus has been to identify new strategies to improve clinical response rates. T cell differentiation status is a critical determinant of response, with stem-like, less differentiated cells demonstrating an enhanced capacity for proliferation and self-renewal following ICB. Given recent data indicating that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (TPEX), we hypothesized that expansion of cDC1s could mediate improved responses to ICB. In our study (Lai, Chan, Armitage et al. Nature Immunol, 2026; https://doi.org/10.1038/s41590-026-02419-4), we identified that Fms-like tyrosine kinase 3 (Flt3L) overexpression increased the proportion of stem-like CD8+ T cluster defined by Tcf7, Sell, and Il7r, using single-cell RNA sequencing analysis. Treatment of mice with Flt3L simultaneously expanded cDC1s and stem-like CD62L+SLAMF6+CD8+ T cells in both tumors and tumor-draining lymph nodes. Interrogating via CRISPR/Cas9-mediated gene deletion, we showed that the formation of these CD62L+SLAMF6+CD8+ T cells is dependent on the transcription factor Myb, CCR7+XCR1+ DCs and lymph node egress, therefore identifying the lymph node as a critical site for Flt3L-mediated T cell differentiation. Combination therapy of Flt3L and anti-CTLA-4 significantly enhanced therapeutic responses and was associated with the emergence of a unique CD8+ T cell subset characterized by the expression of Il21r. These effects were most pronounced with lower affinity tumor-reactive clones, inferring that Flt3L treatment may be particularly effective at broadening the clonality of anti-tumour immune responses. Our work suggests that promoting DC and T cell crosstalk promotes stem-like CD8⁺ T cell differentiation, broadens T cell clonality, and improves ICB efficacy. Targeting this interaction represents a promising approach to improve anti-tumor responses and the efficacy of ICB therapies in cancer patients.