One Third of Malignant Pleural Mesothelioma Shows High Immunohistochemical Expression of MSLN or CXCR4 Which Indicates Potent Candidates for Endo-Radiotherapy

Abstract

Malignant pleural mesothelioma (MPM) is a mainly asbestos-related tumour associated with a very poor prognosis. Therapeutic approaches include multimodal therapy and chemotherapeutics, with cisplatin being the drug of choice, but response rates of only up to 14% indicate very poor outcomes. Effective treatment options are lacking. Besides the diagnostic usage of radioligands in positron emission tomography (PET)/computed tomography (CT), the endo-radioligand therapy with Lu177 has been proven as a powerful tool in cancer therapy. Mesothelin (MSLN) and C-XC chemokine receptor 4 (CXCR4) are membrane-bound proteins, expressed in certain cancers, and thus are promising targets for endo-radiotherapy. A significant portion of high MSLN- or CXCR4-expressing tumors within the MPM may open the field for this sophisticated treatment approach in the near future. Formalin-fixed, paraffin-embedded (FFPE) tumour specimens from 105 patients suffering from MPM and treated at the Lung Cancer Centre of Essen and at the Helios Klinikum Emil von Behring Berlin were screened. The tumour samples were arranged in tissue microarrays. We immunohistochemically stained the tumour samples against MSLN and CXCR4. The protein expressions of the stainings were scored by a pathologist by using a semiquantitative method. The data obtained were correlated with the clinical outcome. Overall, 77.1% of the analysed tumours showed CXCR4 protein expression (25.7% of them at high expression level (Score 3)). 48.6% of all samples showed an overall strong staining (Score ≥ 2), 59% of the investigated tumours showed MSLN protein expression (10.5% of them at high expression (Score 3)), and 36.2% of all samples showed an overall strong staining (Score ≥ 2). Our results show significant tissue expression levels, for both CXCR4 and MSLN protein, in a major portion of clinical MPM samples. One-third of patients showed outstanding immunoexpression of at least one of these markers, making them interesting candidates for radioligand-based PET/CT diagnostics and follow-up and furthermore may profit from endo-radiotherapy.

New Immunohistochemical Markers for Pleural Mesothelioma Subtyping

“…Of note, only patients with Mesothelin membrane staining observed in >50% of tumour cells were included in the study [24]. In this work, the rate of positivity for Mesothelin staining is higher than in previous studies, probably due to the use of different scores and antibodies (e.g., 5B2, MN1, MSVA-235) [14,22,[25][26][27][28]. Only Vizcaya et al used the same clone (i.e., SP74) and found similar results to ours [13].…”

Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma

“…The precursor is cleaved into a soluble peptide called ‘‘megakaryocyte potentiating factor’’ ( 20 ) and a GPI-anchored membrane-bound glycoprotein (mature mesothelin, MSLN) ( 21 , 22 ). Although the MSLN protein is expressed at low levels in HMs, it is overexpressed in asbestos-exposed subjects ( 23 , 24 ) and aberrantly expressed in several solid tumors, including gastric, lung, pancreatic, and ovarian cancers as well as in mesothelioma ( 25 ).…”