Anti-IL-8 antibody activates myeloid cells and potentiates the anti-tumor activity of anti-PD-1 antibody in the humanized pancreatic cancer murine model.

Abstract

Pancreatic ductal adenocarcinoma(PDAC) does not respond to single-agent immune checkpoint inhibitor therapy, including anti-PD-1 antibody(aPD-1) therapy. Higher plasma levels of IL-8 are associated with poorer outcomes in patients who receive aPD-1 therapies, providing a rationale for combination immunotherapy with an anti-IL-8 antibody(aIL-8) and aPD-1. We thus investigated whether human aIL-8 therapy can potentiate the antitumor activity of aPD-1 and further investigated how the combination affects the immune response by regulating myeloid cells in the tumor microenvironment in a humanized murine model of PDAC with a reconstituted immune system consisting of human T cells and a combination of CD14+ and CD16+ myeloid cells. The results show that the combination of aIL-8 and aPD-1 treatment significantly enhanced antitumor activity following the infusion of myeloid cells. Our results further showed that the target of IL-8 is mainly present in CD16+ myeloid cells and is likely to be granulocytes. FACS analysis showed that aIL-8 treatment increased granulocytic myeloid cells in tumors. Consistently, single-nuclear RNA-sequencing analysis of tumor tissue showed that the innate immune response and cytokine response pathways in the myeloid cell cluster were activated by aIL-8 treatment. This is the first preclinical study using a humanized mouse model for new combination immunotherapeutic development and supports the further clinical testing of aIL-8 in combination with aPD-1 for PDAC treatment. This study also suggests that peripherally derived myeloid cells can potentiate the antitumor response of T cells, likely through the innate immune response, and aIL-8 re-educates tumor-infiltrating myeloid cells by activating the innate immune response.

• Authors: Pan Li, Noah Rozich, Jianxin Wang, Junke Wang, Yao Xu, Brian Herbst, Raymond Yu, Stephen Muth, Nan Niu, Keyu Li, Vanessa Funes, Jessica Gai, Arsen Osipov, Barish H Edil, Christopher L Wolfgang, Ming Lei, Tingbo Liang, Lei Zheng
• Journal: Cancer letters (Cancer Lett) Vol. 539 Pg. 215722 (07 28 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 35533951 (Publication Type: Journal Article)
• Copyright: Copyright © 2022. Published by Elsevier B.V.

Chemical References

• Interleukin-8

Topics

• Animals
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism)
• Disease Models, Animal
• Humans
• Interleukin-8
• Mice
• Myeloid Cells (metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Tumor Microenvironment