New York esophageal squamous cell carcinoma-1 and cancer immunotherapy

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Date: Apr. 2015
From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 16,587 words
Lexile Measure: 2150L

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Author(s): Ali Esfandiary aff1 , Soudeh Ghafouri-Fard [*] aff1

Keywords:

cancer-testis antigen; immunogenicity; immunotherapy; NY-ESO-1

The gene coding for New York esophageal squamous cell carcinoma 1 (NY-ESO-1), also known as cancer/testis antigen 1B (CTAG1), is a prototype of cancer testis (CT) gene family. The main characteristics of the members of this family are exclusive or selective expression in the testis among normal tissues and expression in a wide variety of tumors [1 ]. This expression pattern has made them suitable targets for cancer immunotherapy [2,3 ]. Testis is regarded as an immune privileged site due to the presence of a blood-testis barrier. The blood-testis barrier is an outcome of presence of tight junctions between Sertoli cells along the basolateral aspect and between capillary endothelial cells, lack of APCs in seminiferous tubules and absence of HLA class I expression on the surface of germ cells. Therefore, expression of CT genes such as NY-ESO-1 in tissues other than testis can induce immune responses [4 ]. There are now more than 100 gene families with such an expression pattern. Not all of them have been demonstrated to be able of eliciting immune responses but are altogether called the CT antigens (CTAs). Among them, NY-ESO-1 is considered to be the most immunogenic and has become a striking target for cancer vaccine strategies, which would employ the immune system to selectively target and remove the CTA-expressing tumor cells [5 ]. Since its discovery in 1997, NY-ESO-1 has been exemplified as one of the fastest shifts from molecular, cellular and immunological description to clinical trials [6 ].

NY-ESO-1 history & biology

The NY-ESO-1 gene is located on the Xq28 region of the X chromosome and codes for a number of products. This region carries a disproportionately high number of CT genes [7,8 ]. The expression of such CT genes has been shown to be regulated by the demethylation of the promoter regions as well as histone modifications [ 8,9 ]. Recently, it has been demonstrated that the epigenetic regulation of the NY-ESO-1 gene needs the chronological recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes. Therefore, a sequential epigenetic mechanism including the histone deacetylation and methylation, and the DNA methylation processes is involved in this process [10 ]. Antibody against NY-ESO-1 was first found in the serum of a patient with squamous cell carcinoma (SCC) of the esophagus. The method used for such screening is named 'SERological identification of antigens by recombinant EXpression cloning' (SEREX). In this method, serum of cancer-bearing patients is screened against an expression library for identifying the antibody repertoire of the patient [8 ]. NY-ESO-1 is a 180 amino acid long protein of 18 kDa, which contains a glycine-rich N-terminal region and a very hydrophobic C-terminal region. Although its C-terminal structure may imply the presence of a transmembrane domain, there is no evidence of membrane association at the cellular level. Another tumor antigen named LAGE-1 is shown to be strongly homologous to NY-ESO-1. Both NY-ESO-1 and LAGE-1 coding regions have numerous products from alternative reading frames, including a...

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Gale Document Number: GALE|A411322520