PET-based immunomapping of intratumoral CD4+ cells to monitor acquired resistance to checkpoint inhibitors
Year: 2025
Type: article
Abstract: 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 (64Cu-CD4-Nb1) for positron emission tomography (PET). In human CD4-receptor knock-in mice, 64Cu-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.
Authors: Pezzana, Stefania, Blaess, Simone, Traenkle, Bjoern, Schaefer, Anna, Ruoff, Lara, Tako, Bredi, Castaneda Vega, Salvador, Kaiser, Philipp D, Wagner, Teresa, Gonzalez-Menendez, Irene, Quintanilla-Martinez, Leticia, Rochwarger, Alexander, Schürch, Christian M, Riel, Simon, Schaller, Martin, van Genugten, Evelien A J, van der Hoorn, Iris A E, Gorris, Mark A J, Steinvoort, Megan, Peeters, Eva, de Vries, I Jolanda M, van den Heuvel, Michel M, Aarntzen, Erik H J G, Maurer, Andreas, Rothbauer, Ulrich, Pichler, Bernd J, Kneilling, Manfred, Sonanini, Dominik, Longziekten, Cancer, Infection & Immunity
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7149885566