Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer
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; how...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03002-1 |
| _version_ | 1797258932558757888 |
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| author | Fan Yang Chenyang Yuan Fanghui Chen Zhaohui S. Qin Nicole C. Schmitt Gregory B. Lesinski Nabil F. Saba Yong Teng |
| author_facet | Fan Yang Chenyang Yuan Fanghui Chen Zhaohui S. Qin Nicole C. Schmitt Gregory B. Lesinski Nabil F. Saba Yong Teng |
| author_sort | Fan Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T23:01:23Z |
| format | Article |
| id | doaj.art-48f5164039c74ea981c7b089b4993884 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-24T23:01:23Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-48f5164039c74ea981c7b089b49938842024-03-17T12:42:10ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-03-0143111710.1186/s13046-024-03002-1Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancerFan Yang0Chenyang Yuan1Fanghui Chen2Zhaohui S. Qin3Nicole C. Schmitt4Gregory B. Lesinski5Nabil F. Saba6Yong Teng7Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory UniversityDepartment of Biostatistics and Bioinformatics, Rolling School of Public Health, Emory UniversityDepartment of Hematology and Medical Oncology, Winship Cancer Institute, Emory UniversityDepartment of Biostatistics and Bioinformatics, Rolling School of Public Health, Emory UniversityDepartment of Otolaryngology, Emory UniversityDepartment of Hematology and Medical Oncology, Winship Cancer Institute, Emory UniversityDepartment of Hematology and Medical Oncology, Winship Cancer Institute, Emory UniversityDepartment of Hematology and Medical Oncology, Winship Cancer Institute, Emory UniversityAbstract 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.https://doi.org/10.1186/s13046-024-03002-1Head and neck cancerNK cellsIL6 and CCR2scRNA-seqHPVThe tumor microenvironment |
| spellingShingle | Fan Yang Chenyang Yuan Fanghui Chen Zhaohui S. Qin Nicole C. Schmitt Gregory B. Lesinski Nabil F. Saba Yong Teng Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer Journal of Experimental & Clinical Cancer Research Head and neck cancer NK cells IL6 and CCR2 scRNA-seq HPV The tumor microenvironment |
| title | Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer |
| title_full | Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer |
| title_fullStr | Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer |
| title_full_unstemmed | Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer |
| title_short | Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer |
| title_sort | combined il6 and ccr2 blockade potentiates antitumor activity of nk cells in hpv negative head and neck cancer |
| topic | Head and neck cancer NK cells IL6 and CCR2 scRNA-seq HPV The tumor microenvironment |
| url | https://doi.org/10.1186/s13046-024-03002-1 |
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