Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells
Attempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have mostly not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte a...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.918528/full |
| _version_ | 1797990501433999360 |
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| author | Nitya Mohan Nitya Mohan Nitya Mohan Kathrin Wellach Kathrin Wellach Kathrin Wellach Ceren Özerdem Ceren Özerdem Nisha Veits Nisha Veits Jonas D. Förster Jonas D. Förster Jonas D. Förster Sophia Foehr Sophia Foehr Maria Bonsack Maria Bonsack Angelika B. Riemer Angelika B. Riemer |
| author_facet | Nitya Mohan Nitya Mohan Nitya Mohan Kathrin Wellach Kathrin Wellach Kathrin Wellach Ceren Özerdem Ceren Özerdem Nisha Veits Nisha Veits Jonas D. Förster Jonas D. Förster Jonas D. Förster Sophia Foehr Sophia Foehr Maria Bonsack Maria Bonsack Angelika B. Riemer Angelika B. Riemer |
| author_sort | Nitya Mohan |
| collection | DOAJ |
| description | Attempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have mostly not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) class I molecules in different tumor entities, impacts the function of cytotoxic T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and its effect on epitope-specific T cell cytotoxicity. Hypoxia induced downregulation of E7 protein levels in all analyzed cell lines, as assessed by Western blotting. However, contrary to previous reports, no perturbation of antigen processing and presentation machinery (APM) components and HLA-A2 surface expression upon hypoxia treatment was detected by mass spectrometry and flow cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions showed differential effects on the specific killing of HPV16-positive cervical cancer cells by epitope-specific CD8+ T cell lines in a donor- and peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled out by flow cytometry analysis. Altogether, our results under hypoxia show a decreased expression of E6 and E7, but an intact APM, and epitope- and donor-dependent effects on T cell cytotoxicity towards HPV16-positive target cells. This suggests that successful immunotherapies can be developed for hypoxic HPV-induced cervical cancer, with careful choice of target epitopes, and ideally in combination with hypoxia-alleviating measures. |
| first_indexed | 2024-04-11T08:37:35Z |
| format | Article |
| id | doaj.art-58fe8aa9c4544ae69deabc8310f54998 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T08:37:35Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-58fe8aa9c4544ae69deabc8310f549982022-12-22T04:34:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.918528918528Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cellsNitya Mohan0Nitya Mohan1Nitya Mohan2Kathrin Wellach3Kathrin Wellach4Kathrin Wellach5Ceren Özerdem6Ceren Özerdem7Nisha Veits8Nisha Veits9Jonas D. Förster10Jonas D. Förster11Jonas D. Förster12Sophia Foehr13Sophia Foehr14Maria Bonsack15Maria Bonsack16Angelika B. Riemer17Angelika B. Riemer18Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Vaccine Design, German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyImmunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Vaccine Design, German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyImmunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyImmunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyImmunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Vaccine Design, German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyImmunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Vaccine Design, German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, GermanyImmunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Vaccine Design, German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, GermanyImmunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Vaccine Design, German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, GermanyAttempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have mostly not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) class I molecules in different tumor entities, impacts the function of cytotoxic T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and its effect on epitope-specific T cell cytotoxicity. Hypoxia induced downregulation of E7 protein levels in all analyzed cell lines, as assessed by Western blotting. However, contrary to previous reports, no perturbation of antigen processing and presentation machinery (APM) components and HLA-A2 surface expression upon hypoxia treatment was detected by mass spectrometry and flow cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions showed differential effects on the specific killing of HPV16-positive cervical cancer cells by epitope-specific CD8+ T cell lines in a donor- and peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled out by flow cytometry analysis. Altogether, our results under hypoxia show a decreased expression of E6 and E7, but an intact APM, and epitope- and donor-dependent effects on T cell cytotoxicity towards HPV16-positive target cells. This suggests that successful immunotherapies can be developed for hypoxic HPV-induced cervical cancer, with careful choice of target epitopes, and ideally in combination with hypoxia-alleviating measures.https://www.frontiersin.org/articles/10.3389/fimmu.2022.918528/fullHypoxiahuman papillomavirus (HPV)antigen processing and presentation machinery (APM)cytotoxic T cellstumor microenvironment (TME) |
| spellingShingle | Nitya Mohan Nitya Mohan Nitya Mohan Kathrin Wellach Kathrin Wellach Kathrin Wellach Ceren Özerdem Ceren Özerdem Nisha Veits Nisha Veits Jonas D. Förster Jonas D. Förster Jonas D. Förster Sophia Foehr Sophia Foehr Maria Bonsack Maria Bonsack Angelika B. Riemer Angelika B. Riemer Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells Frontiers in Immunology Hypoxia human papillomavirus (HPV) antigen processing and presentation machinery (APM) cytotoxic T cells tumor microenvironment (TME) |
| title | Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells |
| title_full | Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells |
| title_fullStr | Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells |
| title_full_unstemmed | Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells |
| title_short | Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells |
| title_sort | effects of hypoxia on antigen presentation and t cell based immune recognition of hpv16 transformed cells |
| topic | Hypoxia human papillomavirus (HPV) antigen processing and presentation machinery (APM) cytotoxic T cells tumor microenvironment (TME) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.918528/full |
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