Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth
One of the primary obstacles in current cancer treatments lies in the extensive heterogeneity of genetic and epigenetic changes that occur in each arising tumour. However, an additional challenge persists, as certain types of cancer display shared immune deficiencies in the antigen processing machin...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Natural Products |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fntpr.2023.1281061/full |
| _version_ | 1797396993930166272 |
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| author | Samantha L. S. Ellis Samantha L. S. Ellis Samantha L. S. Ellis Samantha L. S. Ellis Lilian L. Nohara Lilian L. Nohara Lilian L. Nohara Sarah Dada Sarah Dada Sarah Dada Sarah Dada Sarah Dada Sarah Dada Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Lonna Munro Lonna Munro Lonna Munro Lonna Munro Kyung Bok Choi Kyung Bok Choi Kyung Bok Choi Kyung Bok Choi Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Cheryl G. Pfeifer Cheryl G. Pfeifer Cheryl G. Pfeifer Cheryl G. Pfeifer David E. Williams Ping Cheng Raymond J. Andersen Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies |
| author_facet | Samantha L. S. Ellis Samantha L. S. Ellis Samantha L. S. Ellis Samantha L. S. Ellis Lilian L. Nohara Lilian L. Nohara Lilian L. Nohara Sarah Dada Sarah Dada Sarah Dada Sarah Dada Sarah Dada Sarah Dada Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Lonna Munro Lonna Munro Lonna Munro Lonna Munro Kyung Bok Choi Kyung Bok Choi Kyung Bok Choi Kyung Bok Choi Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Cheryl G. Pfeifer Cheryl G. Pfeifer Cheryl G. Pfeifer Cheryl G. Pfeifer David E. Williams Ping Cheng Raymond J. Andersen Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies |
| author_sort | Samantha L. S. Ellis |
| collection | DOAJ |
| description | One of the primary obstacles in current cancer treatments lies in the extensive heterogeneity of genetic and epigenetic changes that occur in each arising tumour. However, an additional challenge persists, as certain types of cancer display shared immune deficiencies in the antigen processing machinery (APM). This includes the downregulation of human leukocyte antigen (HLA) class I molecules, which serve as peptide antigen receptors for T lymphocyte recognition that plays a crucial role in killing emerging tumours. Consequently, this contributes to immune escape in metastatic disease. Notably, current cell-based immunotherapies primarily focusing on T lymphocytes and the implementation of immune checkpoint inhibitor modalities have largely ignored the crucial task of reversing immune escape. This oversight may explain the limited success of these approaches becoming more effective cancer immunotherapies. Hence, there is a critical need to prioritize the discovery of new therapeutic candidates that can effectively address immune escape and synergize with evolving immunotherapy strategies. In this context, we identified curcuphenol in a cell-based screen from a library of marine extracts as a chemical entity that reverses the immune-escape phenotype of metastatic cancers. To advance these findings toward clinical efficacy, the present study describes the synthesis of analogues of naturally occurring curcuphenol with enhanced chemical properties and biological efficacy. Here we test the hypothesis that these curcuphenol analogues can evoke the power of the immune system to reduce the growth of metastatic disease in tumour bearing animals. Our findings indicate that these compounds effectively restore the expression of APM genes in metastatic tumours and inhibit the growth of highly invasive tumours in preclinical models, thereby counteracting the common immune evasion phenomenon observed in metastatic cancers. We conclude that cancer immunotherapies capable of boosting APM expression, hold great potential in maximizing the effectiveness of immune blockade inhibitors and eradicating invasive tumours. |
| first_indexed | 2024-03-09T01:03:40Z |
| format | Article |
| id | doaj.art-52baee5274d346a0a2d145329af11432 |
| institution | Directory Open Access Journal |
| issn | 2813-2602 |
| language | English |
| last_indexed | 2024-03-09T01:03:40Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Natural Products |
| spelling | doaj.art-52baee5274d346a0a2d145329af114322023-12-11T12:52:41ZengFrontiers Media S.A.Frontiers in Natural Products2813-26022023-12-01210.3389/fntpr.2023.12810611281061Curcuphenols facilitate the immune driven attenuation of metastatic tumour growthSamantha L. S. Ellis0Samantha L. S. Ellis1Samantha L. S. Ellis2Samantha L. S. Ellis3Lilian L. Nohara4Lilian L. Nohara5Lilian L. Nohara6Sarah Dada7Sarah Dada8Sarah Dada9Sarah Dada10Sarah Dada11Sarah Dada12Iryna Saranchova13Iryna Saranchova14Iryna Saranchova15Iryna Saranchova16Iryna Saranchova17Iryna Saranchova18Lonna Munro19Lonna Munro20Lonna Munro21Lonna Munro22Kyung Bok Choi23Kyung Bok Choi24Kyung Bok Choi25Kyung Bok Choi26Emmanuel Garrovillas27Emmanuel Garrovillas28Emmanuel Garrovillas29Emmanuel Garrovillas30Emmanuel Garrovillas31Emmanuel Garrovillas32Cheryl G. Pfeifer33Cheryl G. Pfeifer34Cheryl G. Pfeifer35Cheryl G. Pfeifer36David E. Williams37Ping Cheng38Raymond J. Andersen39Wilfred A. Jefferies40Wilfred A. Jefferies41Wilfred A. Jefferies42Wilfred A. Jefferies43Wilfred A. Jefferies44Wilfred A. Jefferies45Michael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaDepartment of Microbiology and Immunology, University of British Columbia, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaDepartment of Microbiology and Immunology, University of British Columbia, Vancouver, BC, CanadaVancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, CanadaDepartments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaDepartment of Microbiology and Immunology, University of British Columbia, Vancouver, BC, CanadaVancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, CanadaDepartments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaVancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaVancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaDepartment of Microbiology and Immunology, University of British Columbia, Vancouver, BC, CanadaVancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, CanadaDepartments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaVancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, CanadaSchool of Medicine, Koç University, Istanbul, TürkiyeSchool of Medicine, Koç University, Istanbul, TürkiyeDepartments of Chemistry and Earth Ocean and Atmospheric Sciences, University of British Columbia, Vancouver, BC, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, BC, CanadaCentre for Blood Research, University of British Columbia, Vancouver, BC, CanadaThe Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaDepartment of Microbiology and Immunology, University of British Columbia, Vancouver, BC, CanadaVancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, CanadaDepartments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, CanadaOne of the primary obstacles in current cancer treatments lies in the extensive heterogeneity of genetic and epigenetic changes that occur in each arising tumour. However, an additional challenge persists, as certain types of cancer display shared immune deficiencies in the antigen processing machinery (APM). This includes the downregulation of human leukocyte antigen (HLA) class I molecules, which serve as peptide antigen receptors for T lymphocyte recognition that plays a crucial role in killing emerging tumours. Consequently, this contributes to immune escape in metastatic disease. Notably, current cell-based immunotherapies primarily focusing on T lymphocytes and the implementation of immune checkpoint inhibitor modalities have largely ignored the crucial task of reversing immune escape. This oversight may explain the limited success of these approaches becoming more effective cancer immunotherapies. Hence, there is a critical need to prioritize the discovery of new therapeutic candidates that can effectively address immune escape and synergize with evolving immunotherapy strategies. In this context, we identified curcuphenol in a cell-based screen from a library of marine extracts as a chemical entity that reverses the immune-escape phenotype of metastatic cancers. To advance these findings toward clinical efficacy, the present study describes the synthesis of analogues of naturally occurring curcuphenol with enhanced chemical properties and biological efficacy. Here we test the hypothesis that these curcuphenol analogues can evoke the power of the immune system to reduce the growth of metastatic disease in tumour bearing animals. Our findings indicate that these compounds effectively restore the expression of APM genes in metastatic tumours and inhibit the growth of highly invasive tumours in preclinical models, thereby counteracting the common immune evasion phenomenon observed in metastatic cancers. We conclude that cancer immunotherapies capable of boosting APM expression, hold great potential in maximizing the effectiveness of immune blockade inhibitors and eradicating invasive tumours.https://www.frontiersin.org/articles/10.3389/fntpr.2023.1281061/fullepigenetic modificationantigen processing machinerycurcuphenolmajor histocompatibility complex class Itumoursnatural products |
| spellingShingle | Samantha L. S. Ellis Samantha L. S. Ellis Samantha L. S. Ellis Samantha L. S. Ellis Lilian L. Nohara Lilian L. Nohara Lilian L. Nohara Sarah Dada Sarah Dada Sarah Dada Sarah Dada Sarah Dada Sarah Dada Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Iryna Saranchova Lonna Munro Lonna Munro Lonna Munro Lonna Munro Kyung Bok Choi Kyung Bok Choi Kyung Bok Choi Kyung Bok Choi Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Emmanuel Garrovillas Cheryl G. Pfeifer Cheryl G. Pfeifer Cheryl G. Pfeifer Cheryl G. Pfeifer David E. Williams Ping Cheng Raymond J. Andersen Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Wilfred A. Jefferies Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth Frontiers in Natural Products epigenetic modification antigen processing machinery curcuphenol major histocompatibility complex class I tumours natural products |
| title | Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth |
| title_full | Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth |
| title_fullStr | Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth |
| title_full_unstemmed | Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth |
| title_short | Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth |
| title_sort | curcuphenols facilitate the immune driven attenuation of metastatic tumour growth |
| topic | epigenetic modification antigen processing machinery curcuphenol major histocompatibility complex class I tumours natural products |
| url | https://www.frontiersin.org/articles/10.3389/fntpr.2023.1281061/full |
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