PET-based immunomapping of intratumoral CD4 + cells to monitor acquired resistance to checkpoint inhibitors
- Stefania Pezzana
- Simone Blaess
- Bjoern Traenkle
- Anna Schaefer
- Lara Ruoff
- Bredi Tako
- Salvador Castaneda Vega
- Philipp D. Kaiser
- Teresa Wagner
- Irene Gonzalez-Menendez
- Leticia Quintanilla-Martinez
- Alexander Rochwarger
- Christian M. Schürch
- Simon Riel
- Martin Schaller
- Evelien A. J. van Genugten
- Iris A. E. van der Hoorn
- Mark A. J. Gorris
- Megan Steinvoort
- Eva Peeters
- I. Jolanda M. de Vries
- Michel M. van den Heuvel
- Erik H. J. G. Aarntzen
- Andreas Maurer
- Ulrich Rothbauer
- Bernd J. Pichler
- Manfred Kneilling
- Dominik Sonanini
2025-06-25
CD4 + T cells are crucial in shaping response and resistance to immunotherapy. To enhance our understanding of their multifaceted functions, we developed copper-64–radiolabeled nanobodies targeting the human CD4 receptor ( 64 Cu-CD4-Nb1) for positron emission tomography (PET). In human CD4-receptor knock-in mice, 64 Cu-CD4-Nb1 specifically accumulated in different orthotopic tumors, correlating with histological CD4 + cell densities. Based on intratumoral CD4 + cell distribution patterns within the core and periphery, we distinguished responders to combined αPD-1/4-1BB antibodies early on-treatment. CD4-PET identified resistance to αPD-1 monotherapy, which was mitigated by adding regulatory T cell–depleting α4-1BB antibodies. Patients with early-stage non–small cell lung cancer who relapsed after neoadjuvant αPD-L1 therapy revealed low CD4 + T cell densities in the tumor core. In human and mouse tumor tissues, regulatory T cells correlated with CD4 + cell densities. Thus, visualizing the spatial distribution patterns of CD4 + cells by PET offers mechanistic insights into CD4-mediated therapy efficacy, with great potential for guiding combinatorial immunotherapies in patients with cancer.