Immune Checkpoint Therapy Drives Maturation of a Cellular Neighborhood Nucleated by T Cell-APC Triads Enabling Spatially Compartmentalized Tumor Immunity
Year: 2026
Type: preprint
Abstract: 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: Ruan F. Vieira Medrano, Vladimir Sukhov, Kevin Hoffer-Hawlik, Bar Rozenman, Cora D. Arthur, Fei Han, Bassem Ben Cheikh, Hussein Sultan, Yoshiko Takeuchi, Samuel Ameh, Derek J. Theisen, Yuang Song, Heather N. Kohlmiller, J. Michael White, Alexey Sergushichev, Bernd H. Zinselmeyer, Patrick Leinert, Wm. Patrick Leinert, Kathleen C.F. Sheehan, Garry Nolan, Elham Azizi, Maxim N. Artyomov, Robert D. Schreiber
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7153774073