Introduction:What they say:
A recent study from Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Plesmanlaan, CX Amsterdam, The Netherlands has identified CMTM6 and CMTM4 as PD-L1 protein regulators. This study was published, in the 16 August 2017 issue of Nature (one of the best journals in General science with an impact factor of 43 plus), by Prof Schumacher TNM, Mezzadra R and others. Relating to this finding, a research paper, entitled “CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity”, was published in the same issue of Nature. This research study was conducted by Prof. Mark A. Dawson, Marian L. Burr and others, from Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia; Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge, UK; Centre for Cancer Research, University of Melbourne, Melbourne, Australia; and Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Natural product-derived CMTM6/4-PD-L1 pathway blockade enhances the efficacy of Cancer immunotherapy: A therapeutic mix encompassing Honokiol and Magnolol, isolated from Magnolia grandiflora/dealbata/obovata/officinalis, inhibits the expression of transmembrane protein CMTM6/CMTM4, increases interferon-IFNγ signalling, augments antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival via up-regulation of its target gene
From Significance of the study to Public health relevance:
Given that: (i) PD-1 checkpoint blockade is effective only in minority of cancer patients; (ii) each year nearly 14 million people are diagnosed with cancer globally; (iii) cancer deaths globally are expected to be doubled in the next decade; (iv) metastasis is the principle reason for most of the cancer deaths; (v) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) an effective way to activate patients’ immune system against tumors (Cancer immunotherapy); (ii) a way to improve the efficacy of immunotherapy by targeting more than one immune evasion molecules; (iii) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iv) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (v) a cheaper alternative to the existing expensive anticancer drugs; (vi) a side-effect-free natural product-based drug; (vii) increase the therapeutic index of anti-cancer drugs; and (viii) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.
What is known?
It has recently been shown that blocking cell surface receptor PD-1 with antibodies one could make tumors shrink. This work, relating to Cancer immunotherapy, has been chosen as Science’s breakthrough of the year recently.
Profs. Mark A. Dawson, Schumacher TNM and their research team members have shown that CMTM6/4 (a T-III transmembrane protein): (1) function as positive regulators of programmed death-1 (PD-1) ligand 1 (PD-L1)[(also known as CD274 or B7-H1] (and they’ve used a genome-wide CRISPR–Cas9 screen and a haploid genetic screen to identify them); (2) co-localize with PD-L1 protein at the plasma transmembrane; and maintain its cell surface expression; (3) stabilize PD-L1 by decreasing its ubiquitination; (4) prevent PD-L1 from lysosome-mediated degradation; (5) increase PD-L1 half-life; (6) depletion decrease PD-L1 levels; and (7) augment the ability of PD-L1 to inhibit T-cells, suggesting that inhibition of CMTM6/4 may decrease the levels of PD-L1 and enhance the efficacy of cancer immunotherapy.
From Research Findings to Therapeutic opportunity:
A therapeutic mix encompassing Honokiol and Magnolol, by increasing the expression of its target genes, it may decrease CMTM6/4 and Glycogen synthase kinase 3-ß expression (fig. 1). Thereby, it may: (i) diminish the expression of a number of immune evasion molecules in cancer cells; (ii) increase IFNγ signaling; (iii) increase transcription factor T-bet expression; (iv) increase antigen presentation; (v) increase CD8(+) cytotoxic T lymphocyte function; (vi) augment unfolded protein response; (vii) augment the number of tumor-infiltrating immune cells; (viii) increase T-cell anti-tumor immunity; (ix) decrease tumor burden and promote growth suppression; (x) inhibit metastatic cancer progression; (xi) increase survival of patients with cancers; and (xii) increase the efficacy of immunotherapy (fig. 1).
Thus, pharmacological formulations encompassing “Honokiol and Magnolol or their analogues either alone or in combination with any of the known anticancer agents“ may be used to (i) inhibit the progression of metastatic tumors; and (ii) enhance the efficacy of Cancer immunotherapy.
Details of the research findings:
Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.
Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/
Amount: $1, 500
Undisclosed mechanistic information: How Honokiol and Magnolol suppress the expression of CMTM6/4 and augment anti-tumor immunity
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# Research cooperation
Citation: Boominathan, L., Natural product-derived CMTM6/4-PD-L1 pathway blockade enhances the efficacy of Cancer immunotherapy: Honokiol, isolated from Magnolia-grandiflora/dealbata/obovata/officinalis, inhibits the expression of transmembrane protein CMTM6/CMTM4, increases interferon-IFN? signalling, increases antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival via up-regulation of its target gene, 19/August/2017, 11.58 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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