Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated With Genomic Tumor Changes Which Can Result in Transdifferentiation
| Autor: | Maxime Hamon, Luc Xerri, Frédéric Escudié, Charlotte Syrykh, Peggy Dartigues, Lénaïg Mescam, José Adélaïde, Marie Parrens, Caroline Besson, Pierre Sujobert, Gael Jalowicki, Alexandre Bardet, Thierry Molina, Daniel Birnbaum, Camille Laurent, Frédéric Fina, Arnaud Guille |
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| Rok vydání: | 2021 |
| Předmět: |
Biology
medicine.disease_cause Immunotherapy Adoptive Pathology and Forensic Medicine Proto-Oncogene Proteins p21(ras) Phosphatidylinositol 3-Kinases immune system diseases medicine Humans Gene B cell In Situ Hybridization Fluorescence Comparative Genomic Hybridization medicine.diagnostic_test Genomics medicine.disease Burkitt Lymphoma Chimeric antigen receptor Lymphoma medicine.anatomical_structure DNA methylation Cell Transdifferentiation Cancer research Surgery KRAS Lymphoma Large B-Cell Diffuse Anatomy Neoplasm Recurrence Local Comparative genomic hybridization Fluorescence in situ hybridization Transcription Factors |
| Zdroj: | The American journal of surgical pathology. 46(6) |
| ISSN: | 1532-0979 |
| Popis: | Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy (CART) in B-cell non-Hodgkin lymphomas, durable responses are uncommon. The histopathologic and molecular features associated with treatment failure are still largely unknown. Therefore, we have analyzed 19 sequential tumor samples from 9 patients, prior anti-CD19 CART (pre-CART) and at relapse (post-CART), using immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, next-generation DNA and RNA sequencing, and genome-scale DNA methylation. The initial diagnosis was diffuse large B-cell lymphoma (n=6), double-hit high-grade B-cell lymphoma (n=1), and Burkitt lymphoma (n=2). Histopathologic features were mostly retained at relapse in 7/9 patients, except the frequent loss of 1 or several B-cell markers. The remaining 2 cases (1 diffuse large B-cell lymphoma and 1 Burkitt lymphoma) displayed a dramatic phenotypic shift in post-CART tumors, with the drastic downfall of B-cell markers and emergence of T-cell or histiocytic markers, despite the persistence of identical clonal immunoglobulin gene rearrangements. The post-CART tumor with aberrant T-cell phenotype showed reduced mRNA expression of most B-cell genes with increased methylation of their promoter. Fluorescence in situ hybridization and comparative genomic hybridization showed global stability of chromosomal alterations in all paired samples, including 17p/TP53 deletions. New pathogenic variants acquired in post-CART samples included mutations triggering the PI3K pathway (PIK3R1, PIK3R2, PIK3C2G) or associated with tumor aggressiveness (KRAS, INPP4B, SF3B1, SYNE1, TBL1XR1). These results indicate that CART-resistant B-cell non-Hodgkin lymphomas display genetic remodeling, which may result in profound dysregulation of B-cell differentiation. Acquired mutations in the PI3K and KRAS pathways suggest that some targeted therapies could be useful to overcome CART resistance. |
| Databáze: | OpenAIRE |
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