Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma

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Assis-Mendonca, Guilherme Rossi ^[1] ; Fattori, Andre ^[2] ; Rocha, Rafael Malagoli ^[3] ; Lourenco, Gustavo Jacob ^[4] ; Delamain, Marcia Torresan ^[5] ; Nonogaki, Suely ^[6] ; Cordeiro de Lima, Vladmir Claudio ^[7] ; Braga Colleoni, Gisele Wally ^[8] ; de Souza, Carmino Antonio ^{[2, 5]} ; Soares, Fernando Augusto ^[9] ; Passos Lima, Carmen Silvia ^{[2, 4]} ; Vassallo, Jose ^{[1, 9, 10]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Dept Pathol, Fac Med Sci, Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Dept Internal Med, Fac Med Sci, Campinas, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Gynecol, Mol Gynecol Lab, Sao Paulo - Brazil

^[4] Univ Estadual Campinas, Lab Canc Genet, Fac Med Sci, Campinas, SP - Brazil

^[5] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Campinas - Brazil

^[6] Secretaria Estado Saude Sao Paulo, Inst Adolfo Lutz, Sao Paulo, SP - Brazil

^[7] AC Camargo Canc Ctr, Dept Med Oncol, Sao Paulo - Brazil

^[8] Univ Fed Sao Paulo, Dept Clin & Expt Oncol, Sao Paulo, SP - Brazil

^[9] Rede DOr Hosp Network, Pathol Div, Sao Paulo, SP - Brazil

^[10] Univ Estadual Campinas, Lab Invest & Mol Pathol LIP, CIPED, Fac Med Sci, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BMC CANCER; v. 21, n. 1 MAR 1 2021.
• Citações Web of Science: 0

Resumo

BackgroundThere is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL.MethodsWe assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models.ResultsHigh FOXP3/CD3 ratios (p =0.001), high IL17A levels (p =0.003) and low IL2 levels (p =0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p =0.02). In the SNV model, the CC haplotype of IL10 (p <0.01), the GG genotype of IL2 rs2069762 (p=0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p <0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGF beta levels (p =0.03) and less CD163+ macrophages (p =0.01), but did not modulate patients' survival.ConclusionsOur results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations. (AU)

• Processo FAPESP: 14/09854-5 - Microambiente tumoral em linfomas não-Hodgkin indolentes: impacto de microRNAs tumorais e polimorfismos inflamatórios nos aspectos clínicos e patológicos
• Beneficiário: José Vassallo
• Modalidade de apoio: Auxílio à Pesquisa - Regular