TY - JOUR
T1 - PET-based immunomapping of intratumoral CD4+ cells to monitor acquired resistance to checkpoint inhibitors
AU - Pezzana, Stefania
AU - Blaess, Simone
AU - Traenkle, Bjoern
AU - Schaefer, Anna
AU - Ruoff, Lara
AU - Tako, Bredi
AU - Vega, Salvador Castaneda
AU - Kaiser, Philipp D.
AU - Wagner, Teresa
AU - Gonzalez-Menendez, Irene
AU - Quintanilla-Martinez, Leticia
AU - Rochwarger, Alexander
AU - Schürch, Christian M.
AU - Riel, Simon
AU - Schaller, Martin
AU - van Genugten, Evelien A.J.
AU - van der Hoorn, Iris A.E.
AU - Gorris, Mark A.J.
AU - Steinvoort, Megan
AU - Peeters, Eva
AU - de Vries, I. M.Jolanda
AU - van den Heuvel, Michel M.
AU - Aarntzen, Erik H.J.G.
AU - Maurer, Andreas
AU - Rothbauer, Ulrich
AU - Pichler, Bernd J.
AU - Kneilling, Manfred
AU - Sonanini, Dominik
N1 - Publisher Copyright:
Copyright © 2025 The Authors, some rights reserved;
PY - 2025/6/27
Y1 - 2025/6/27
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105009785517
U2 - 10.1126/sciadv.adw1924
DO - 10.1126/sciadv.adw1924
M3 - Article
C2 - 40561008
AN - SCOPUS:105009785517
SN - 2375-2548
VL - 11
JO - Science Advances
JF - Science Advances
IS - 26
M1 - eadw1924
ER -