Immune Checkpoint Therapy Drives Maturation of a Cellular Neighborhood Nucleated by T Cell-APC Triads Enabling Spatially Compartmentalized Tumor Immunity
Spatially organized immune hubs of T cells and antigen-presenting cells (APCs) have been linked to immune checkpoint therapy (ICT) efficacy, yet the mechanisms underlying their function remain unclear. Using CODEX multiplex imaging, we longitudinally characterized the dynamic evolution of intratumoral cellular neighborhoods (CN) defined by triad interactions of CD4 and CD8 T cells with two distinct myeloid APC populations: cDC1s and IFN-gamma-activated macrophages. We termed this CN the immunity-promoting CN (IP-CN) and tracked its progressive development during tumor rejection induced by anti-CTLA-4/anti-PD-1 therapy. A coordinated IFN-gamma; and TNF-alpha signaling signature accompanied the IP-CN assembly. Over time, the IP-CN underwent functional maturation, forming specialized sub-neighborhoods that compartmentalized proliferating T cells at the tumor periphery versus cytotoxic T effector cells interacting with tumor cell targets. Our findings reveal a spatiotemporal mechanism by which the IP-CN sustains and amplifies cytotoxic T cell responses, demonstrating how T cell-APC neighborhoods orchestrate tumor immunity.
Authors
- Yuang Song
- Bernd H. Zinselmeyer (ORCID: https://orcid.org/0000-0003-4172-6767)
- Hussein Sultan (ORCID: https://orcid.org/0000-0003-4067-8169)
- Bassem Ben Cheikh
- Yoshiko Takeuchi (ORCID: https://orcid.org/0000-0002-2637-7696)
- Garry P. Nolan (ORCID: https://orcid.org/0000-0002-8862-9043)
- Derek J. Theisen (ORCID: https://orcid.org/0000-0002-2204-8676)
- Vladimir Sukhov (ORCID: https://orcid.org/0000-0002-5169-1433)
- Alexey Sergushichev (ORCID: https://orcid.org/0000-0003-1159-7220)
- Cora D. Arthur
- Patrick Leinert
- Kathleen C. F. Sheehan (ORCID: https://orcid.org/0000-0002-3357-8285)
- Elham Azizi (ORCID: https://orcid.org/0000-0001-5059-6971)
- Robert D. Schreiber (ORCID: https://orcid.org/0000-0003-1590-2341)
- Maxim N. Artyomov (ORCID: https://orcid.org/0000-0002-1133-4212)
- Kevin Hoffer-Hawlik
- Samuel Ameh
- Ruan FV Medrano
- Bar Rozenman
- J. Michael White
- Heather N Kohlmiller
- Fei Han
Institutions
- Saint Barnabas Medical Center (US)
- TiGenix (Spain) (ES)
- Parker Institute for Cancer Immunotherapy (US)
- Rescon Technologies (United Kingdom) (GB)
- Washington School of Psychiatry (US)
- Akoya Biosciences (United States) (US)
- Columbia University (US)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-12
- DOI
- https://doi.org/10.64898/2026.04.08.716779
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Parker Institute for Cancer Immunotherapy