Irene Fusi, Clara Serger, Petra Herzig, Markus Germann, Michael T. Sandholzer1, Nicole Oelgarth1, Petra C. Schwalie, Leyla Don, Viola K. Vetter, Viktor H. Koelzer, Didier Lardinois, Henry Kao, Laura Codarri Deak, Pablo Umaña, Christian Klein, Aljaz Hojski, Marina Natoli, Alfred Zippelius
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引用次数: 0
Abstract
Antibody-cytokine fusion proteins are being developed as next-generation cancer immunotherapies, aiming to deliver activation signals to targeted immune populations. Among these, PD1-IL2v—an engineered interleukin-2 variant (IL-2v) lacking CD25 binding, fused to a high-affinity programmed cell death protein 1 (PD-1) blocking antibody—has shown promising results in murine tumor models. Here, using human model systems, we show that PD1-IL2v elicits a multifaceted antitumor T cell response by targeting both CD8+ and conventional CD4+ T (Tconv) cells. Single-cell RNA sequencing (scRNAseq) on a lung cancer patient–derived tumor fragment (PDTF) platform revealed that PD1-IL2v drives the expansion of proliferative, cytotoxic CD8+ T cells exhibiting features of tumor reactivity. This was accompanied by up-regulation of CXCR6, enhancing their migratory capacity. In Tconv cells, PD1-IL2v up-regulated CXCL13 expression and promoted a T follicular helper/T helper 1 (TFH/TH1)–like transcriptional program associated with anti-PD1 responsiveness. Our findings provide mechanistic insights into the effects of IL-2v–targeted delivery to PD-1+ cells within human tumors, supporting the clinical development of next-generation immunocytokines.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.