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CKLF like MARVEL transmembrane domain containing 6

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CMTM6
Identifiers
AliasesCMTM6, CKLFSF6, PRO2219, CKLF like MARVEL transmembrane domain containing 6, ayoube, gourari
External IDsOMIM: 607889; MGI: 2447165; HomoloGene: 9845; GeneCards: CMTM6; OMA:CMTM6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

54918

67213

Ensembl

ENSG00000091317

ENSMUSG00000032434

UniProt

Q9NX76

Q9CZ69

RefSeq (mRNA)

NM_017801

NM_026036

RefSeq (protein)

NP_060271

NP_080312

Location (UCSC)Chr 3: 32.48 – 32.5 MbChr 9: 114.56 – 114.58 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] CMTM6 protein belongs to the CKLF-like MARVEL transmembrane domain-containing family of proteins.[6] This family consist of 9 member proteins: CKLF and CMTM1 through CMTM8.[7][8] The CMTM family proteins are involved in autoimmune diseases, cardiovascular diseases, the male reproductive system, haematopoiesis, and cancer development.[8] CMTM6 protein regulates immune responses to normal and abnormal (particularly cancerous) cells.[9][10]

Structure and locations

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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[11] 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.[8]

Functions and actions

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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.[11] 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[11]) 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.[12]

Therapeutic inhibition of CMTM6's actions

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Various manufactured therapeutic monoclonal antibody drugs, e.g. pembrolizumab,[12] atezolizumab, durvalumab[13] nivolumab,[14] and avelumab,[9] 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,[14] triple-negative breast cancers,[15] undifferentiated pleomorphic sarcomas, and some forms of soft tissue sarcomas that have metastasized.[16] 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.[17] 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 severe 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.[18]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000091317 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032434 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "CMTM6 CKLF like MARVEL transmembrane domain-containing 6 [Homo sapiens (Human)] - Gene - NCBI".
  6. ^ Han W, Ding P, Xu M, Wang L, Rui M, Shi S, Liu Y, Zheng Y, Chen Y, Yang T, Ma D (June 2003). "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. doi:10.1016/s0888-7543(03)00095-8. PMID 12782130.
  7. ^ Lu J, Wu QQ, Zhou YB, Zhang KH, Pang BX, Li L, Sun N, Wang HS, Zhang S, Li WJ, Zheng W, Liu W (2016). "Cancer Research Advance in CKLF-like MARVEL Transmembrane Domain-Containing Member Family (Review)". Asian Pacific Journal of Cancer Prevention. 17 (6): 2741–4. PMID 27356683.
  8. ^ a b c Wu J, Li L, Wu S, Xu B (August 2020). "CMTM family proteins 1-8: roles in cancer biological processes and potential clinical value". Cancer Biology & Medicine. 17 (3): 528–542. doi:10.20892/j.issn.2095-3941.2020.0032. PMC 7476098. PMID 32944388.
  9. ^ a b Ribas A, Wolchok JD (March 2018). "Cancer immunotherapy using checkpoint blockade". Science. 359 (6382): 1350–1355. Bibcode:2018Sci...359.1350R. doi:10.1126/science.aar4060. PMC 7391259. PMID 29567705.
  10. ^ "Entrez Gene: CKLF like MARVEL transmembrane domain-containing 6". Retrieved 2017-10-23.
  11. ^ a b c Burr ML, Sparbier CE, Chan YC, Williamson JC, Woods K, Beavis PA, Lam EY, Henderson MA, Bell CC, Stolzenburg S, Gilan O, Bloor S, Noori T, Morgens DW, Bassik MC, Neeson PJ, Behren A, Darcy PK, Dawson SJ, Voskoboinik I, Trapani JA, Cebon J, Lehner PJ, Dawson MA (September 2017). "CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity". Nature. 549 (7670): 101–105. Bibcode:2017Natur.549..101B. doi:10.1038/nature23643. PMC 5706633. PMID 28813417.
  12. ^ a b Mazarico Gallego JM, Herrera Juárez M, Paz-Ares L (March 2020). "The safety and efficacy of pembrolizumab for the treatment of non-small cell lung cancer". Expert Opinion on Drug Safety. 19 (3): 233–242. doi:10.1080/14740338.2020.1736554. PMID 32129104. S2CID 212405175.
  13. ^ Huo X, Shen G, Liu Z, Liang Y, Li J, Zhao F, Ren D, Zhao J (December 2021). "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. doi:10.1016/j.critrevonc.2021.103530. PMID 34801695.
  14. ^ a b Chen J, Wang J, Xu H (April 2021). "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. doi:10.1097/MD.0000000000025180. PMC 8051984. PMID 33847617.
  15. ^ Latif F, Bint Abdul Jabbar H, Malik H, Sadaf H, Sarfraz A, Sarfraz Z, Cherrez-Ojeda I (December 2021). "Atezolizumab and pembrolizumab in triple-negative breast cancer: a meta-analysis". Expert Review of Anticancer Therapy. 22 (2): 229–235. doi:10.1080/14737140.2022.2023011. PMID 34949142. S2CID 245482969.
  16. ^ Monga V, Skubitz KM, Maliske S, Mott SL, Dietz H, Hirbe AC, Van Tine BA, Oppelt P, Okuno S, Robinson S, O'Connor M, Seetharam M, Attia S, Charlson J, Agulnik M, Milhem M (July 2020). "A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas". Cancers. 12 (7): 1873. doi:10.3390/cancers12071873. PMC 7408640. PMID 32664595.
  17. ^ Tanizaki J, Yonemori K, Akiyoshi K, Minami H, Ueda H, Takiguchi Y, Miura Y, Segawa Y, Takahashi S, Iwamoto Y, Kidera Y, Fukuoka K, Ito A, Chiba Y, Sakai K, Nishio K, Nakagawa K, Hayashi H (November 2021). "Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary". Annals of Oncology. 33 (2): 216–226. doi:10.1016/j.annonc.2021.11.009. PMID 34843940. S2CID 244691795.
  18. ^ Larbouret C, Gros L, Pèlegrin A, Chardès T (September 2021). "Improving Biologics' Effectiveness in Clinical Oncology: From the Combination of Two Monoclonal Antibodies to Oligoclonal Antibody Mixtures". Cancers. 13 (18): 4620. doi:10.3390/cancers13184620. PMC 8465647. PMID 34572847.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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