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

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

doi:10.1016/j.canlet.2022.215722

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

Cancer Lett. 2022 Jul 28:539:215722. doi: 10.1016/j.canlet.2022.215722. Epub 2022 May 7.

Authors

Pan Li¹, Noah Rozich², Jianxin Wang¹, Junke Wang³, Yao Xu³, Brian Herbst³, Raymond Yu⁴, Stephen Muth³, Nan Niu³, Keyu Li³, Vanessa Funes³, Jessica Gai³, Arsen Osipov⁵, Barish H Edil⁶, Christopher L Wolfgang⁷, Ming Lei⁸, Tingbo Liang⁹, Lei Zheng¹⁰

Affiliations

¹ The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Department of Surgery, and the Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Department of Surgery, and the Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; University of Oklahoma, Oklahoma City, OK, USA.
³ The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Department of Surgery, and the Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ NovaRock, Biotherapeutics Ltd., Ewing, NJ, USA.
⁵ The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Department of Surgery, and the Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cedar-Sinai Medical Center, Los Angeles, CA, USA.
⁶ University of Oklahoma, Oklahoma City, OK, USA.
⁷ The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Department of Surgery, and the Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; New York University, New York, NY, USA.
⁸ NovaRock, Biotherapeutics Ltd., Ewing, NJ, USA. Electronic address: Ming.Lei@novarockbio.com.
⁹ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: liangtingbo@zju.edu.cn.
¹⁰ The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Department of Surgery, and the Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: lzheng6@jhmi.edu.

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.

Keywords: Anti-IL-8 antibody; Anti-PD-1 antibody; Humanized pancreatic cancer models; Myeloid cells; Reconstituted immune system.

MeSH terms

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

Substances

Interleukin-8

Abstract

MeSH terms

Substances

Grants and funding