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Article

CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response

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Predictive Oncology Laboratory, Equipe Labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University, 13009 Marseille, France
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Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille University, CNRS, INSERM, 13009 Marseille, France
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Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy
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Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center of Postgraduate Education, 01-813 Warsaw, Poland
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Department of Genetics, Maria Sklodowska-Curie National Institute of Oncology, 02-781 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Maria Cristina Sini
Cancers 2022, 14(5), 1306; https://doi.org/10.3390/cancers14051306
Received: 28 January 2022 / Revised: 28 February 2022 / Accepted: 2 March 2022 / Published: 3 March 2022
(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors)
Gastrointestinal stromal tumors (GIST) are the most frequent sarcomas of the gastrointestinal tract. Identification of novel prognostic and/or therapeutic targets is a major issue to overcome tyrosine kinase inhibitors resistances. CSPG4, a cell surface proteoglycan, emerged as a potential therapeutic target for immune therapy in different cancers, including sarcomas. CSPG4 expression has never been studied in GIST. In this work we analyzed CSPG4 mRNA expression in a large series of clinical GIST samples given the scarcity of disease (n = 309 patients). We find that high CSPG4 expression is independently associated with disease-free survival, and with an immune landscape favorable to induce strong cytotoxic immune response after NK cell stimulation. Our results suggest the potential value of CSPG4-specific chimeric antigen receptor-redirected cytokine-induced killer lymphocytes treatment in GIST, notably “CSPG4-high” tumors, and calls for preclinical validation, drug testing in vivo, then in clinical trials.
The treatment of gastrointestinal stromal tumors (GIST) must be improved through the development of more reliable prognostic factors and of therapies able to overcome imatinib resistance. The immune system represents an attractive tool. CSPG4, a cell surface proteoglycan, emerged as a potential therapeutic target for immune therapy in different cancers, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in sarcomas. CSPG4 expression has never been studied in GIST. We analyzed CSPG4 mRNA expression data of 309 clinical GIST samples profiled using DNA microarrays and searched for correlations with clinicopathological and immune features. CSPG4 expression, higher in tumors than normal digestive tissues, was heterogeneous across tumors. High expression was associated with AFIP low-risk, gastric site, and localized stage, and independently with longer postoperative disease-free survival (DFS) in localized stage. The correlations between CSPG4 expression and immune signatures highlighted a higher anti-tumor immune response in “CSPG4-high” tumors, relying on both the adaptive and innate immune system, in which the boost of NK cells by CSPG4-CAR.CIKs might be instrumental, eventually combined with immune checkpoint inhibitors. In conclusion, high CSPG4 expression in GIST is associated with better DFS and offers an immune environment favorable to a vulnerability to CAR.CIKs. View Full-Text
Keywords: CSPG4; gene expression; GIST; immune response; prognosis; CAR-CIKs; NK cells CSPG4; gene expression; GIST; immune response; prognosis; CAR-CIKs; NK cells
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MDPI and ACS Style

de Nonneville, A.; Finetti, P.; Picard, M.; Monneur, A.; Pantaleo, M.A.; Astolfi, A.; Ostrowski, J.; Birnbaum, D.; Mamessier, E.; Bertucci, F. CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response. Cancers 2022, 14, 1306. https://doi.org/10.3390/cancers14051306

AMA Style

de Nonneville A, Finetti P, Picard M, Monneur A, Pantaleo MA, Astolfi A, Ostrowski J, Birnbaum D, Mamessier E, Bertucci F. CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response. Cancers. 2022; 14(5):1306. https://doi.org/10.3390/cancers14051306

Chicago/Turabian Style

de Nonneville, Alexandre, Pascal Finetti, Maelle Picard, Audrey Monneur, Maria A. Pantaleo, Annalisa Astolfi, Jerzy Ostrowski, Daniel Birnbaum, Emilie Mamessier, and François Bertucci. 2022. "CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response" Cancers 14, no. 5: 1306. https://doi.org/10.3390/cancers14051306

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