Journal Article

DKFZ-2025-01294

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PET-based immunomapping of intratumoral CD4+ cells to monitor acquired resistance to checkpoint inhibitors.

Pezzana, S. ; Blaess, S. ; Traenkle, B. ; Schaefer, A. ; Ruoff, L. ; Tako, B. ; Castaneda Vega, S. ; Kaiser, P. D. ; Wagner, T. ; Gonzalez-Menendez, I. ; Quintanilla-Martinez, L. ; Rochwarger, A. ; Schürch, C. M. ; Riel, S. ; Schaller, M. ; van Genugten, E. A. J. ; van der Hoorn, I. A. E. ; Gorris, M. A. J. ; Steinvoort, M. ; Peeters, E. ; de Vries, I. J. M. ; van den Heuvel, M. M. ; Aarntzen, E. H. J. G. ; Maurer, A. ; Rothbauer, U. ; Pichler, B.DKFZ* ; Kneilling, M. ; Sonanini, D.DKFZ*

2025
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.adw1924

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.

Keyword(s): Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Positron-Emission Tomography: methods (MeSH) ; CD4-Positive T-Lymphocytes: immunology (MeSH) ; CD4-Positive T-Lymphocytes: metabolism (MeSH) ; Immune Checkpoint Inhibitors: pharmacology (MeSH) ; Immune Checkpoint Inhibitors: therapeutic use (MeSH) ; Drug Resistance, Neoplasm: immunology (MeSH) ; T-Lymphocytes, Regulatory: immunology (MeSH) ; Copper Radioisotopes: chemistry (MeSH) ; Carcinoma, Non-Small-Cell Lung: immunology (MeSH) ; Carcinoma, Non-Small-Cell Lung: drug therapy (MeSH) ; Carcinoma, Non-Small-Cell Lung: diagnostic imaging (MeSH) ; Cell Line, Tumor (MeSH) ; Lung Neoplasms: immunology (MeSH) ; Lung Neoplasms: diagnostic imaging (MeSH) ; Lung Neoplasms: drug therapy (MeSH) ; Single-Domain Antibodies: immunology (MeSH) ; Immunotherapy (MeSH) ; Immune Checkpoint Inhibitors ; Copper Radioisotopes ; Single-Domain Antibodies ; Copper-64

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Tübingen (TU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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