Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells
Abstract Background It has been proposed that cancer establishment, maintenance, and recurrence may be attributed to a unique population of tumor cells termed cancer-initiating cells (CICs) that may include characteristics of putative cancer stem cell-like cells. Studies in lung cancer have shown th...
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| Format: | Article |
| Language: | English |
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BMC
2018-04-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12885-018-4389-3 |
| _version_ | 1819101691356643328 |
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| author | Brian J. Morrison Jason C. Steel John C. Morris |
| author_facet | Brian J. Morrison Jason C. Steel John C. Morris |
| author_sort | Brian J. Morrison |
| collection | DOAJ |
| description | Abstract Background It has been proposed that cancer establishment, maintenance, and recurrence may be attributed to a unique population of tumor cells termed cancer-initiating cells (CICs) that may include characteristics of putative cancer stem cell-like cells. Studies in lung cancer have shown that such cells can be enriched and propagated in vitro by culturing tumor cells in serum-free suspension as tumorspheres. CICs have been characterized for their phenotype, stem cell-like qualities, and their role in establishing tumor and maintaining tumor growth. Less is known about the interaction of CICs with the immune system. Methods We established CIC-enriched tumorspheres from murine TC-1 lung cancer cells, expressing human papillomavirus 16 (HPV-16) E6/E7 antigens, and evaluated their susceptibility to antitumor immune responses both in vitro and in vivo. Results TC-1 CICs demonstrated reduced expression of surface major histocompatibility complex (MHC)-I molecules compared to non-CICs. We similarly determined decreased MHC-I expression in five of six human lung cancer cell lines cultured under conditions enriching for CICs. In vivo, TC-1 cells enriched for CICs were resistant to human papillomavirus 16 E6/E7 peptide vaccine-mediated killing. We found that vaccinated mice challenged with CIC enriched tumorspheres demonstrated shorter survivals and showed significantly fewer CD8+ tumor infiltrating lymphocytes compared to CIC non-enriched challenged mice. Furthermore, cultured cytotoxic T lymphocytes (CTLs) from vaccinated mice demonstrated reduced capacity to lyse TC-1 cells enriched for CICs compared to non-enriched TC-1 cells. Following treatment with IFN-γ, both CIC enriched and non-enriched TC-1 cells expressed similar levels of MHC-I, and the increased MHC-I expression on CICs resulted in greater CTL-mediated tumor lysis and improved tumor-free survival in mice. Conclusions These results suggest that the attenuated expression of MHC-I molecules by CICs represents a potential strategy of CICs to escape immune recognition, and that the development of successful immunotherapy strategies targeting CICs may decrease their resistance to T cell-mediated immune detection by enhancing CIC MHC-I expression. |
| first_indexed | 2024-12-22T01:22:41Z |
| format | Article |
| id | doaj.art-7e02f236f5284faebdcc42ac1d59b3de |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-22T01:22:41Z |
| publishDate | 2018-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-7e02f236f5284faebdcc42ac1d59b3de2022-12-21T18:43:42ZengBMCBMC Cancer1471-24072018-04-0118111010.1186/s12885-018-4389-3Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cellsBrian J. Morrison0Jason C. Steel1John C. Morris2Viral and Rickettsial Diseases Department, Infectious Diseases Directorate, Naval Medical Research CenterFaculty of Medicine, The University of QueenslandDivision of Hematology-Oncology, University of Cincinnati Cancer Institute, University of CincinnatiAbstract Background It has been proposed that cancer establishment, maintenance, and recurrence may be attributed to a unique population of tumor cells termed cancer-initiating cells (CICs) that may include characteristics of putative cancer stem cell-like cells. Studies in lung cancer have shown that such cells can be enriched and propagated in vitro by culturing tumor cells in serum-free suspension as tumorspheres. CICs have been characterized for their phenotype, stem cell-like qualities, and their role in establishing tumor and maintaining tumor growth. Less is known about the interaction of CICs with the immune system. Methods We established CIC-enriched tumorspheres from murine TC-1 lung cancer cells, expressing human papillomavirus 16 (HPV-16) E6/E7 antigens, and evaluated their susceptibility to antitumor immune responses both in vitro and in vivo. Results TC-1 CICs demonstrated reduced expression of surface major histocompatibility complex (MHC)-I molecules compared to non-CICs. We similarly determined decreased MHC-I expression in five of six human lung cancer cell lines cultured under conditions enriching for CICs. In vivo, TC-1 cells enriched for CICs were resistant to human papillomavirus 16 E6/E7 peptide vaccine-mediated killing. We found that vaccinated mice challenged with CIC enriched tumorspheres demonstrated shorter survivals and showed significantly fewer CD8+ tumor infiltrating lymphocytes compared to CIC non-enriched challenged mice. Furthermore, cultured cytotoxic T lymphocytes (CTLs) from vaccinated mice demonstrated reduced capacity to lyse TC-1 cells enriched for CICs compared to non-enriched TC-1 cells. Following treatment with IFN-γ, both CIC enriched and non-enriched TC-1 cells expressed similar levels of MHC-I, and the increased MHC-I expression on CICs resulted in greater CTL-mediated tumor lysis and improved tumor-free survival in mice. Conclusions These results suggest that the attenuated expression of MHC-I molecules by CICs represents a potential strategy of CICs to escape immune recognition, and that the development of successful immunotherapy strategies targeting CICs may decrease their resistance to T cell-mediated immune detection by enhancing CIC MHC-I expression.http://link.springer.com/article/10.1186/s12885-018-4389-3Cancer stem cellsCancer-initiating cellsAnimal modelsLung cancerMajor histocompatibility complex-ICytotoxic T lymphocytes |
| spellingShingle | Brian J. Morrison Jason C. Steel John C. Morris Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells BMC Cancer Cancer stem cells Cancer-initiating cells Animal models Lung cancer Major histocompatibility complex-I Cytotoxic T lymphocytes |
| title | Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells |
| title_full | Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells |
| title_fullStr | Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells |
| title_full_unstemmed | Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells |
| title_short | Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells |
| title_sort | reduction of mhc i expression limits t lymphocyte mediated killing of cancer initiating cells |
| topic | Cancer stem cells Cancer-initiating cells Animal models Lung cancer Major histocompatibility complex-I Cytotoxic T lymphocytes |
| url | http://link.springer.com/article/10.1186/s12885-018-4389-3 |
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