Fusi and Serger et al. showed that PD-1–IL2v, comprising a PD-1 blocking antibody and an IL-2Rα-non-binding IL-2 variant, induced antitumor T cell activity in human PBMCs and CD8+ and CD4+Foxp3- TILs in vitro. ScRNAseq of lung cancer patient-derived tumor fragments showed that PD-1–IL2v induced CD8+ T cell expression of CXCR6 (increasing migration in vitro) and cytotoxic, proliferative, tumor-reactive effector programs, as well as CD4+Foxp3- T cell expression of CXCL13, and a TFH/TH1 profile associated with immune cell recruitment, TLS formation, and cytotoxicity.
Contributed by Paula Hochman
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 (T(conv)) 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 T(conv) cells, PD1-IL2v up-regulated CXCL13 expression and promoted a T follicular helper/T helper 1 (T(FH)/T(H)1)-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.
Author Info: (1) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. (2) Department of Biomedicine, University Hospital Basel and University o
Author Info: (1) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. (2) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. (3) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. (4) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. (5) (6) (7) Roche Pharma Research and Early Development, Discovery Oncology, Roche Innovation Center Zurich, 8952 Schlieren, Switzerland. (8) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. (9) Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland. (10) Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland. Institute of Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland. (11) Department of Thoracic Surgery, University Hospital Basel, 4031 Basel, Switzerland. (12) Roche Pharma Research and Early Development, Early Development Oncology Biomarkers, Roche Innovation Center Basel, 4070 Basel, Switzerland. (13) Roche Pharma Research and Early Development, Discovery Oncology, Roche Innovation Center Zurich, 8952 Schlieren, Switzerland. (14) Roche Pharma Research and Early Development, Discovery Oncology, Roche Innovation Center Zurich, 8952 Schlieren, Switzerland. (15) Roche Pharma Research and Early Development, Discovery Oncology, Roche Innovation Center Zurich, 8952 Schlieren, Switzerland. Department of Biochemistry, Faculty of Chemistry and Pharmacy, Ludwig Maximilians University of Munich, 81377 Munich, Germany. (16) Department of Thoracic Surgery, University Hospital Basel, 4031 Basel, Switzerland. (17) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. (18) Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland.
