Biology:CKLF like MARVEL transmembrane domain containing 6
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CKLF like MARVEL transmembrane domain-containing 6 (i.e. CMTM6), previously termed chemokine-like factor superfamily 6 (i.e. CKLFSF6), is a transmembrane protein encoded in humans by the CMTM6 gene (also termed the CKLFSF6, PRO2219, ayoube, or gourari gene). This gene is located in band 22.3 on the short (or "p") arm of chromosome 3.[1] CMTM6 protein belongs to the CKLF-like MARVEL transmembrane domain-containing family of proteins.[2] This family consist of 9 member proteins: CKLF and CMTM1 through CMTM8.[3][4] The CMTM family proteins are involved in autoimmune diseases, cardiovascular diseases, the male reproductive system, haematopoiesis, and cancer development.[4] CMTM6 protein regulates immune responses to normal and abnormal (particularly cancerous) cells.[5][6]
Structure and locations
Like the other members in the CMTM protein family, CMTM6 has a structure that contains domains (i.e. parts) similar to those in chemokine proteins; tetraspanin proteins (also termed transmembrane-4 superfamily proteins); the myelin and lymphocyte protein (also termed MAR protein); proteins that direct membrane vesicle trafficking; and proteins that are embedded across cell membranes. CMTM6 proteins are expressed in virtually all tissues[7] and are located in cell plasma membranes (i.e. cell surface membranes), lysosomes, endosomes, cytosol, attached to the cell's cytoskeleton, and in extracellular spaces.[4]
Functions and actions
CMTM6 localizes with and binds to cell PD-L1 protein located on cell surface membranes thereby maintaining PD-L1'S expression at this site; it also localizes with PD-L1 protein located in recycling endosomes and thereby prevents PD-L1 from being degraded by lysosomal enzymes. These actions increase and maintain high levels of PD-L1 on cell surface membranes.[7] PD-L1 protein on the surface of normal cells binds to PD-1 receptors on a type of cytotoxic T cells (i.e. CD8+ T cells[7]) and thereby blocks these T-cells from organizing an immune response that would kill them. This PD-L1/CD8+ T cell circuit is one of several immune checkpoint mechanisms for maintaining self-tolerance, i.e. for preventing CD8+ T cells from attacking normal cells. Tumor cells may employ this immune-evading tactic: they may express PD-L1 and thereby block CD8+ T cell-mediated immune responses to themselves. In effect, the robust expression of PD-L1 helps not only normal cells but also cancer cells to evade immune destruction.[8]
Therapeutic inhibition of CMTM6's actions
Various manufactured therapeutic monoclonal antibody drugs, e.g. pembrolizumab,[8] atezolizumab, durvalumab[9] nivolumab,[10] and avelumab,[5] bind to and inhibit the stimulation of PD-1 on CD8+ T cells by PD-L1. In effect, they block the ability of CMTMT6 to suppress PDL1/PD-1-stimulated CD8+ T-cell immune responses against tumor cells. One or more of these drugs are approved by the FDA for treating (as a single agent or in combination with adjuvant radiotherapy and/or chemotherapy) various cancers including certain types of Hodgkin's disease, melanomas, Merkel-cell carcinomas, cancers associated with microsatellite instability (e.g. certain types of colon, stomach, endometrial, ovarian, hepatobiliary tract, urinary tract, brain, and skin cancers), non-small cell lung cancer, head and neck cancers, esophageal cancers, bladder cancers, urinary track cancers, renal cell cancers, hepatocellular carcinomas,[10] triple-negative breast cancers,[11] undifferentiated pleomorphic sarcomas, and some forms of soft tissue sarcomas that have metastasized.[12] A phase II study of 56 patients with cancer of unknown primary origin, i.e. a very common (2% to 5% of all diagnosed cancers) and difficult to treat metastatic cancer in which the primary cancer is unknown) found that nivolumab had a small (overall complete plus partial response rate of ~20%) beneficial effect.[13] However, the use of any of these monoclonal antibody drugs as a single immunotherapy agent often benefits only a small percentage of cases with a particular disease, often lasts for only a short time, and may cause sever side-effects. Consequently, alternate methods of using these anti-PD-1 antibodies are being studied. Current preclinical studies and clinical trials are testing combinations of two anti-PD-1 antibodies or one anti-PD-1 antibody combined with an antibody that binds to and inhibits other immune response-regulating proteins, e.g. the CTLA4 protein (i.e. cytotoxic T-lymphocyte-associated protein 4), for their therapeutic effects in the just cited and other cancer types.[14]
References
- ↑ "CMTM6 CKLF like MARVEL transmembrane domain-containing 6 [Homo sapiens (Human)] - Gene - NCBI". https://www.ncbi.nlm.nih.gov/gene/54918.
- ↑ "Identification of eight genes encoding chemokine-like factor superfamily members 1-8 (CKLFSF1-8) by in silico cloning and experimental validation". Genomics 81 (6): 609–17. June 2003. doi:10.1016/s0888-7543(03)00095-8. PMID 12782130.
- ↑ "Cancer Research Advance in CKLF-like MARVEL Transmembrane Domain-Containing Member Family (Review)". Asian Pacific Journal of Cancer Prevention 17 (6): 2741–4. 2016. PMID 27356683.
- ↑ 4.0 4.1 4.2 "CMTM family proteins 1-8: roles in cancer biological processes and potential clinical value". Cancer Biology & Medicine 17 (3): 528–542. August 2020. doi:10.20892/j.issn.2095-3941.2020.0032. PMID 32944388.
- ↑ 5.0 5.1 "Cancer immunotherapy using checkpoint blockade". Science 359 (6382): 1350–1355. March 2018. doi:10.1126/science.aar4060. PMID 29567705. Bibcode: 2018Sci...359.1350R.
- ↑ "Entrez Gene: CKLF like MARVEL transmembrane domain-containing 6". https://www.ncbi.nlm.nih.gov/gene/54918.
- ↑ 7.0 7.1 7.2 "CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity". Nature 549 (7670): 101–105. September 2017. doi:10.1038/nature23643. PMID 28813417. Bibcode: 2017Natur.549..101B.
- ↑ 8.0 8.1 "The safety and efficacy of pembrolizumab for the treatment of non-small cell lung cancer". Expert Opinion on Drug Safety 19 (3): 233–242. March 2020. doi:10.1080/14740338.2020.1736554. PMID 32129104.
- ↑ "Addition of immunotherapy to chemotherapy for metastatic triple-negative breast cancer: A systematic review and meta-analysis of randomized clinical trials". Critical Reviews in Oncology/Hematology 168: 103530. December 2021. doi:10.1016/j.critrevonc.2021.103530. PMID 34801695.
- ↑ 10.0 10.1 "Comparison of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with extensive-stage small cell lung cancer: A systematic review and network meta-analysis". Medicine 100 (15): e25180. April 2021. doi:10.1097/MD.0000000000025180. PMID 33847617.
- ↑ "Atezolizumab and pembrolizumab in triple-negative breast cancer: a meta-analysis". Expert Review of Anticancer Therapy 22 (2): 229–235. December 2021. doi:10.1080/14737140.2022.2023011. PMID 34949142.
- ↑ "A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas". Cancers 12 (7): 1873. July 2020. doi:10.3390/cancers12071873. PMID 32664595.
- ↑ "Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary". Annals of Oncology 33 (2): 216–226. November 2021. doi:10.1016/j.annonc.2021.11.009. PMID 34843940.
- ↑ "Improving Biologics' Effectiveness in Clinical Oncology: From the Combination of Two Monoclonal Antibodies to Oligoclonal Antibody Mixtures". Cancers 13 (18): 4620. September 2021. doi:10.3390/cancers13184620. PMID 34572847.
Further reading
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
![]() | Original source: https://en.wikipedia.org/wiki/CKLF like MARVEL transmembrane domain containing 6.
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