Frontiers in Natural Products (Dec 2023)
Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth
- 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
Affiliations
- Samantha L. S. Ellis
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Samantha L. S. Ellis
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Samantha L. S. Ellis
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Samantha L. S. Ellis
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Lilian L. Nohara
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Lilian L. Nohara
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Lilian L. Nohara
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Sarah Dada
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Sarah Dada
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Sarah Dada
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Sarah Dada
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Sarah Dada
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
- Sarah Dada
- Departments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- Iryna Saranchova
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Iryna Saranchova
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Iryna Saranchova
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Iryna Saranchova
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Iryna Saranchova
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
- Iryna Saranchova
- Departments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
- Kyung Bok Choi
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
- Emmanuel Garrovillas
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Emmanuel Garrovillas
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Emmanuel Garrovillas
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Emmanuel Garrovillas
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Emmanuel Garrovillas
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
- Emmanuel Garrovillas
- Departments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
- David E. Williams
- School of Medicine, Koç University, Istanbul, Türkiye
- Ping Cheng
- School of Medicine, Koç University, Istanbul, Türkiye
- Raymond J. Andersen
- Departments of Chemistry and Earth Ocean and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Departments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- DOI
- https://doi.org/10.3389/fntpr.2023.1281061
- Journal volume & issue
-
Vol. 2
Abstract
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.
Keywords
- epigenetic modification
- antigen processing machinery
- curcuphenol
- major histocompatibility complex class I
- tumours
- natural products
