Journal of Clinical Chemistry and Laboratory Medicine
Open Access

Mesothelin: An Immunotherapy Target

Wu Wiu De^{* *}Correspondence: Wu Wiu De, Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medial Sciences, Beijing, 100730, China, Email:

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Introduction

Mesothelin (MSLN) is first discovered by Chang et al. in 1992, a membrane bound surface glycoprotein which is encoded by MSLN gene located on human chromosome 16p.13.3, is exceptionally expressed in various solid tumors such as pancreatic adenocarcinoma, threatening pleural mesothelioma, and ovarian cancer, however in certain limited kinds of normal tissues including pleura, peritoneum, pericardium, and epithelium of trachea. Because of its differential articulation among malignant growth and typical tissues and its part in tumorigenesis, MSLN can be viewed as an expected objective for OC. The mature form of MSLN is shed from the cell membrane by TNF-α-converting enzyme (TACE, also known as ADAM17); the fragmented part is known as Soluble Mesothelin-Related Peptide (SMRP) [1]. The soluble isoform is due to an abnormal splicing phase of the intron present between exons 16 and 17 which lead to a frameshift mutation and premature termination at amino acid and deletion of the amino acids at the C-terminal that are responsible for membrane bounding [2].

Functions of mesothelin

Mesothelin is typically confined to the mesothelial cells of pericardium, pleura, peritoneum, and tunica vaginalis. It is repeated as a restricted expression of MSLN present in epithelial cells of tonsils and trachea, and inner lining of fallopian tubes; while it is over expressed in numerous solid tumors, including, mesothelioma, epithelial OC, lung adenocarcinoma, cholangiocarcinoma, PDAC and triple-negative breast malignancy. The outflow of MSLN isoforms in by far most of OC, just as in different tumors, demonstrates that they might have organic capacities in tumor cells. Despite this, the natural capacity of MSLN isn't completely perceived. Moreover, MPF was simply found to animate the megakaryocyte colony-forming activity within the sight of interleukin-3 (IL-3) in mouse bone marrow cell, while MPF alone didn't have any inborn stimulating activity [3].

The immunogenicity of mesothelin is related to its high expression on tumor cells. Increased levels of MSLN-specific IgG antibodies can be detected by ELISA (Enzyme-Linked Immunosorbent Assay). In a study conducted by Chang et al., MSLN was observed to aid in migrating and invasive capacity of OC cells both in vitro and in vivo by stimulating the expression of MMP-7 (Matrix Metalloproteinase) via activating MAPK (Mitogen-Activated Protein Kinase) or ERK (Extracellular Signal Regulated Kinase) and c-Jun N-Terminal Kinase (JNK) signaling pathway. The regulation of MMP 7 gene transcription is induced by MSLN can be facilitated by Activator Protein-1(AP-1) transcription factor [4].

CAR-T therapy

Chimeric Antigen Receptor T (CAR-T) cells are intended to target cell surface antigens without MHC (major histocompatibility complex) limitation. Consequently, the CART cells could be extensively applicable in HLA-assorted allogeneic recipients. The CARs are recombinant receptors regularly comprising of an extracellular antigen recognition domain, which is derived from the single chain variable fragment (scFv) of antibodies, transmembrane areas that anchors in the cytoplasmic layer, and an intracellular domain that sends T cell activation signals. The 1st generation CARs comprised of just a single intracellular signaling domain, which was normally a CD3z chain, and this was adequate to initiate T cell activation yet delivered only short term proliferative action and a low degree of cytotoxicity.

MSLN-directed CAR-T cells induce cytotoxicity in MSLNexpressing pancreatic malignancy cells in vivo relying upon the MSLN activation level to delay tumor development and eliminate lung metastases in vivo. MSLN was likewise a promising objective for treating cellular breakdown in the lungs and gastric malignancy. The third-generation CAR-T could viably delay tumor development or even totally kill subcutaneous tumors, eliminate respiratory and intraperitoneal metastases of gastric malignancy cells in mice and draw out endurance [5]. CAR-T cells are produced through lentivirus transduction. The CAR genes are cloned into lentiviral vectors and consequently incorporated into the host T cell genome, considering the steady and perpetual activation of the CAR. This strategy has been broadly embraced on the grounds that it is reliable and simple. Another strategy utilized for the steady combination of the CAR quality into the T cell genome is the piggyBac transposon system/framework. The piggyBac transposon system is an effective non-viral technique for the genomic designing of mammalian cells, including pluripotent stem cells and human T lymphocytes, and its benefits incorporate a huge payload limit, nonrandom integration and the elimination of virus associated tissues. CAR-T cells administered by systemic delivery like intravenous infusion. Notwithstanding, systemically delivered T cells need to go through the hindrances made by numerous tissues prior to penetrating into tumors. Hence, insufficient T cell penetration and short persistence are obstacles in solid tumor treatment via CAR-T [6].

Detection of MSLN (Mesothelin)

Mesothelin might be utilized as valuable analytic marker on proof that it is effectively shed for cell surface making a pool of antigens in blood flow or ascites, taking into account the measurement of circulating serum MSLN levels utilizing blood ELISA tests. Mesothelin was decidedly recognized in various histopathological types of OC, particularly in serous OC [7]. Mesothelin has been investigated as an objective for molecular imaging tests intended to evaluate tumor uptake, circulation in primary and secondary tumor sites, and response to treatment. Mesothelin imaging has been applied with different anti-MSLN antibodies in animal models.

Conclusion

Mesothelin, expressed in OC, assumes significant roles in cellular adhesion, tumor metastasis, and drug resistance. At any rate, the system is still ineffectively comprehended, which require further examinations. The regular expression of MSLN in typical and malignant growth tissues makes it a promising objective for conclusion of remedial applications. Although a few clinical investigations are in progress to examine the safety and adequacy of MSLN-designated drugs with or without other synthetic specialists, including CAR-T cells, immunotoxin, antibody-drug conjugates, and antibodies, the restorative impact appears to be moderate for most systems. Future examination and clinical trials in novel MSLN-targeting treatments to improve the cytotoxic and antitumor viability yet with minor side effects are critically required.

References

1. Sapede C, Gauvrit A, Barbieux I, Padieu M, Cellerin L, Sagan C, et al. Aberrant splicing and protease involvement in mesothelin release from epithelioid mesothelioma cells. Cancer Sci. 2008;99(3):590-594.
2. Shen J, Sun X, Zhou J. Insights into the Role of Mesothelin as a Diagnostic and Therapeutic Target in Ovarian Carcinoma. Front Oncol. 2020;10:1263.
3. Chang K, Pastan I, Willingham MC. Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int. J Cancer Res. 1992;50(3):373-381.
4. Chang MC, Chen CA, Chen PJ, Chiang YC, Chen YL, Mao TL, et al. Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways. Biochem J. 2012;442(2):293-302.
5. Lv J, Zhao R, Wu D, Zheng D, Wu Z, Shi J, et al. Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer. J Hematol Oncol. 2019;12(1):1-4.
6. He J, Zhang Z, Lv S, Liu X, Cui L, Jiang D, et al. Engineered CAR T cells targeting mesothelin by piggyBac transposon system for the treatment of pancreatic cancer.       Cell Immunol.2018;329:31-40.
7. Ordóñez NG. Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 2003;27(11):1418-1428.