1. Academic Validation
  2. Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer

Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer

  • J Exp Clin Cancer Res. 2024 Mar 12;43(1):76. doi: 10.1186/s13046-024-03002-1.
Fan Yang # 1 Chenyang Yuan # 2 Fanghui Chen 1 Zhaohui S Qin 2 Nicole C Schmitt 3 Gregory B Lesinski 1 Nabil F Saba 1 Yong Teng 4 5 6
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 201 Dowman Dr, Atlanta, GA, 30322, USA.
  • 2 Department of Biostatistics and Bioinformatics, Rolling School of Public Health, Emory University, Atlanta, GA, 30322, USA.
  • 3 Department of Otolaryngology, Emory University, Atlanta, GA, 30322, USA.
  • 4 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 201 Dowman Dr, Atlanta, GA, 30322, USA. yong.teng@emory.edu.
  • 5 Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA. yong.teng@emory.edu.
  • 6 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA. yong.teng@emory.edu.
  • # Contributed equally.
Abstract

Background: While T cell-activating immunotherapies against recurrent head and neck squamous cell carcinoma (HNSCC) have shown impressive results in clinical trials, they are often ineffective in the majority of patients. NK cells are potential targets for immunotherapeutic intervention; however, the setback in monalizumab-based therapy in HNSCC highlights the need for an alternative treatment to enhance their antitumor activity.

Methods: Single-cell RNA Sequencing (scRNA-seq) and TCGA HNSCC datasets were used to identify key molecular alterations in NK cells. Representative HPV-positive ( +) and HPV-negative ( -) HNSCC cell lines and orthotopic mouse models were used to validate the bioinformatic findings. Changes in immune cells were examined by flow cytometry and immunofluorescence.

Results: Through integration of scRNA-seq data with TCGA data, we found that the impact of IL6/IL6R and CCL2/CCR2 signaling pathways on evasion of immune attack by NK cells is more pronounced in the HPV - HNSCC cohort compared to the HPV + HNSCC cohort. In orthotopic mouse models, blocking IL6 with a neutralizing antibody suppressed HPV - but not HPV + tumors, which was accompanied by increased tumor infiltration and proliferation of CD161+ NK cells. Notably, combining the CCR2 Chemokine Receptor antagonist RS504393 with IL6 blockade resulted in a more pronounced antitumor effect that was associated with more activated intratumoral NK cells in HPV - HNSCC compared to either agent alone.

Conclusions: These findings demonstrate that dual blockade of IL6 and CCR2 pathways effectively enhances the antitumor activity of NK cells in HPV-negative HNSCC, providing a novel strategy for treating this type of Cancer.

Keywords

Double blockade; HPV; Head and neck cancer; IL6 and CCR2; NK cells; The tumor microenvironment; scRNA-seq.

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