Guilherme Rossi Assis-Mendonça1, André Fattori2, Rafael Malagoli Rocha3, Gustavo Jacob Lourenço4, Márcia Torresan Delamain5, Suely Nonogaki6, Vladmir Cláudio Cordeiro de Lima7, Gisele Wally Braga Colleoni8, Cármino Antonio de Souza2,5, Fernando Augusto Soares9, Carmen Silvia Passos Lima2,4, José Vassallo10,9,11. 1. Department of Pathology, Faculty of Medical Sciences, University of Campinas, Distrito de Barão Geraldo, Campinas, SP, Brazil. guilhermeram13@yahoo.com.br. 2. Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil. 3. Molecular Gynecology Laboratory, Department of Gynecology, Federal University of São Paulo, São Paulo, Brazil. 4. Laboratory of Cancer Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil. 5. Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil. 6. Instituto Adolfo Lutz, Secretaria de Estado da Saúde, São Paulo, SP, Brazil. 7. Department of Medical Oncology, A C Camargo Cancer Center, São Paulo, Brazil. 8. Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo, SP, Brazil. 9. Rede D'Or Hospitals Network - Pathology Division, São Paulo, SP, Brazil. 10. Department of Pathology, Faculty of Medical Sciences, University of Campinas, Distrito de Barão Geraldo, Campinas, SP, Brazil. 11. Laboratory of Investigative and Molecular Pathology (LIP), CIPED, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
Abstract
BACKGROUND: There 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. METHODS: We 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. RESULTS: High 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 TGFβ levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival. CONCLUSIONS: Our 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.
BACKGROUND: There 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. METHODS: We 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. RESULTS: High 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 IL2rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1rs6957 associated with lower tumor TGFβ levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival. CONCLUSIONS: Our 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.
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