Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors.

Abstract

BACKGROUNDS:

In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.

METHODS:

Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype.

RESULTS:

TNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells.

CONCLUSIONS:

Anti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall.

• Authors: Xiaozhen Zhang, Mengyi Lao, Jian Xu, Yi Duan, Hanshen Yang, Muchun Li, Honggang Ying, Lihong He, Kang Sun, Chengxiang Guo, Wen Chen, Haitao Jiang, Xiaoyu Zhang, Xueli Bai, Tingbo Liang
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 10 Issue 3 (03 2022) ISSN: 2051-1426 [Electronic] England
• PMID: 35260434 (Publication Type: Journal Article)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Chemical References

• B7-H1 Antigen
• Programmed Cell Death 1 Receptor
• Receptors, Tumor Necrosis Factor, Type II

Topics

• Animals
• B7-H1 Antigen
• Carcinoma, Pancreatic Ductal (therapy)
• Humans
• Immunotherapy
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Pancreatic Neoplasms
• Programmed Cell Death 1 Receptor
• Receptors, Tumor Necrosis Factor, Type II
• Tumor Microenvironment
• Pancreatic Neoplasms