Research Papers:

An integrative microenvironment approach for follicular lymphoma: roles of inflammatory cell subsets and immune-response polymorphisms on disease clinical course

Guilherme Rossi Assis-Mendonça _, André Fattori, Rafael Malagoli Rocha, Gustavo Jacob Lourenço, Márcia Torresan Delamain, Suely Nonogaki, Vladmir Cláudio Cordeiro de Lima, Gisele Wally Braga Colleoni, Cármino Antonio de Souza, Fernando Augusto Soares, Carmen Silvia Passos Lima and José Vassallo

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Oncotarget. 2020; 11:3153-3173. https://doi.org/10.18632/oncotarget.27698

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Guilherme Rossi Assis-Mendonça1,2, André Fattori3, Rafael Malagoli Rocha4, Gustavo Jacob Lourenço5, Márcia Torresan Delamain6, Suely Nonogaki7, Vladmir Cláudio Cordeiro de Lima8, Gisele Wally Braga Colleoni9, Cármino Antonio de Souza3,6, Fernando Augusto Soares10, Carmen Silvia Passos Lima3,5 and José Vassallo1,2,10

1 Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil

2 Laboratory of Investigative and Molecular Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil

3 Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil

4 Molecular Gynecology Laboratory, Department of Gynecology, Federal University of São Paulo, São Paulo, Brazil

5 Laboratory of Cancer Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil

6 Hematology and Hemotherapy Center, University of Campinas, Campinas, São Paulo, Brazil

7 Instituto Adolfo Lutz, Secretaria de Estado da Saúde, São Paulo, Brazil

8 Department of Medical Oncology, AC Camargo Cancer Center, São Paulo, Brazil

9 Federal University of São Paulo, São Paulo, Brazil

10 Rede D'Or Hospitals-Pathology Department, São Paulo, Brazil

Correspondence to:

Guilherme Rossi Assis-Mendonça,email: [email protected]

Keywords: follicular lymphoma; tumor microenvironment; immunohistochemistry; single nucleotide polymorphisms; prognosis

Received: March 11, 2020     Accepted: July 14, 2020     Published: August 18, 2020


The study of the tumor microenvironment (TME) in follicular lymphoma (FL) has produced conflicting results due to assessment of limited TME subpopulations, and because of heterogeneous treatments among different cohorts. Also, important genetic determinants of immune response, such as single-nucleotide polymorphisms (SNPs), remain underexplored in this disease.

We performed a detailed study of the TME in 169 FL biopsies using immunohistochemistry, encompassing lymphocytes, macrophages, and cytokines. We also genotyped 16 SNPs within key immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, and IL17F) in 159 patients. We tested associations between SNPs, clinicopathological features and TME composition, and proposed survival models in R-CHOP/R-CVP-treated patients.

Presence of the IL12A rs568408 “A” allele associated with the follicular pattern of FOXP3+ cells. The IL12A AA haplotype included rs583911 and rs568408 and was an independent predictor of worse survival, together with the follicular patterns of T-cells (FOXP3+ and CD8+) and high IL-17F tumor levels. The patterns of CD3+, CD4+ and CD8+ cells, displayed as a principal component, also associated with survival. Hierarchical clustering of the TME proteins demonstrated a cluster that was associated with worse prognosis (tumors enriched in IL-17A, IL-17F, CD8, PD1, and Ki-67).

The survival of FL patients who were treated in the rituximab era shows a strong dependence on TME signals, especially the T-cell infiltration patterns and IL-17F tumor levels. The presence of the AA haplotype of IL12A in the genome of FL patients is an additional prognostic factor that may modulate the composition of T-reg cells in this disease.

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