A novel cell-based screen identifies chemical entities that reverse the immune-escape phenotype of metastatic tumours

Abstract

Genetic and epigenetic events have been implicated in the downregulation of the cellular antigen processing and presentation machinery (APM), which in turn, has been associated with cancer evasion of the immune system. When these essential components are lacking, cancers develop the ability to subvert host immune surveillance allowing cancer cells to become invisible to the immune system and, in turn, promote cancer metastasis. Here we describe and validate the first high-throughput cell-based screening assay to identify chemical extracts and unique chemical entities that reverse the downregulation of APM components in cell lines derived from metastatic tumours. Through the screening of a library of 480 marine invertebrate extracts followed by bioassay-guided fractionation, curcuphenol, a common sesquiterpene phenol derived from turmeric, was identified as the active compound of one of the extracts. We demonstrate that curcuphenol induces the expression of the APM components, TAP-1 and MHC-I molecules, in cell lines derived from both metastatic prostate and lung carcinomas. Turmeric and curcumins that contain curcuphenol have long been utilized not only as a spice in the preparation of food, but also in traditional medicines for treating cancers. The remarkable discovery that a common component of spices can increase the expression of APM components in metastatic tumour cells and, therefore reverse immune-escape mechanisms, provides a rationale for the development of foods and advanced nutraceuticals as therapeutic candidates for harnessing the power of the immune system to recognize and destroy metastatic cancers.

Curcuphenol possesses an unusual histone deacetylase enhancing activity that counters immune escape in metastatic tumours

“…We previously used a high-throughput cell-based screening assay to identify chemical entities that reverse the downregulation of APM components in cell lines derived from metastatic tumours. We discovered that one of these entities, curcuphenol, induces the expression of the APM components, TAP-1 and MHC-I molecules, in cell lines derived from both metastatic prostate and lung carcinomas ( Nohara et al, 2023 ). We therefore treated A9 metastatic cells with curcuphenol and IFN-γ and analyzed them via RT-PCR.…”

“…Cancer is a devastating disease that arises from genetic mutations and epigenetic modifications that govern cell proliferation, apoptosis, senescence, and invasion ( Alimonti et al, 2000 ; Setiadi et al, 2005a ; Nguyen and Massagué, 2007a ; Setiadi et al, 2007a ; Esteller, 2008 ; Setiadi et al, 2008a ; Seliger et al, 2012 ; Saranchova et al, 2016 ; Saranchova et al, 2018 ; Dhatchinamoorthy et al, 2021a ; Dada et al, 2023 ; Nohara et al, 2023 ). A common signature shared by invasive forms of metastatic cancers originating from many different tissues, is the loss of immunogenicity that consequently results in immune evasion ( Alimonti et al, 2000 ; Shankaran et al, 2001 ; Setiadi et al, 2005a ; Lou et al, 2007 ; Setiadi et al, 2007a ; Setiadi et al, 2008a ; Saranchova et al, 2016 ; Saranchova et al, 2018 ; Dhatchinamoorthy et al, 2021a ; Dada et al, 2023 ; Nohara et al, 2023 ). This can be achieved through several mechanisms, one of which involves evasion through the loss of the antigen presentation machinery (APM), a process known as immune escape or immunoediting.…”

“…HDACs play crucial roles in biological processes including cell proliferation, apoptosis, inflammation, and in molecular processes associated with cancer ( Chen et al, 2015 ; Li et al, 2021 ; Song et al, 2021 ; Xu et al, 2021 ; Borcoman et al, 2022 ). Additionally, we previously discovered that treatment with HDAC inhibitors resulted in the re-establishment of the APM expression and function and also reduces tumour growth in vivo , surprisingly indicating that the loss of the APM expression can be reversed ( Setiadi et al, 2005a ; Setiadi et al, 2007a ; Setiadi et al, 2008a ; Saranchova et al, 2016 ; Saranchova et al, 2018 ; Dada et al, 2023 ; Nohara et al, 2023 ).…”

“…Curcuphenol naturally occurs in plants and some marine sponges and is a component of culinary spices including cumin and turmeric that are used in medicinal ethnobiology and ethnopharmacology as traditional medicines and as dietary supplements ( Paul and Sa, 2021 ; Dada et al, 2023 ). We previously discovered that cannabinoids and curcuphenol are able to reverse the immune escape phenotype of metastatic tumours in vitro ( Dada et al, 2023 ; Nohara et al, 2023 ). Here we test the hypothesis that curcuphenol and synthetic analogues of curcuphenol, possess a previously undescribed HDAC inhibitory activity, that reverses immune escape by resurrecting APM expression in metastatic tumours and therefore, underpins curcuphenol’s anti-metastasis activity.…”

Curcuminoids as Anticancer Drugs: Pleiotropic Effects, Potential for Metabolic Reprogramming and Prospects for the Future

“…First, new active natural molecules belonging to this family are continuously being discovered in the world. To mention just a few, in the search for new marine anticancer drugs, and in a context of global climate change that could affect bioresources [ 249 ], the potential of new molecules extracted from marine invertebrates that have an ability to reverse the immune-escape phenotype in metastatic tumors has just started [ 250 ]. With respect to the third question discussed above, new biologically active derivatives produced through microbial transformation of curcuminoids (diarylheptanoids) isolated from natural resources are also being studied [ 251 ].…”