Page 135 - Haematologica - Vol. 105 n. 6 - June 2020

Non-Hodgkin Lymphoma
The architecture of neoplastic follicles in follicular lymphoma; analysis of the relationship between the tumor and follicular helper T cells
William Townsend,1,2 Marta Pasikowska,1 Deborah Yallop,1,3 Elizabeth H. Phillips,1 Piers E.M. Patten,1,3 Jonathan R. Salisbury,4 Robert Marcus,3 Andrea Pepper,5# and Stephen Devereux1,3#
1Department of Haematological Medicine, Rayne Institute, King’s College London, London; 2Department of Haematology, University College London Hospitals NHS Foundation Trust, London; 3Department of Haematology, King’s College Hospital, London; 4Department of Histopathology, King’s College Hospital, London and 5Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK
#AP and SD are senior co-authors.
ABSTRACT
CD4+ T-follicular helper cells are essential for the survival, proliferation, and differentiation of germinal center B cells and have been implicat- ed in the pathogenesis of follicular lymphoma (FL). To further define the role of these cells in FL, we used multiparameter confocal microscopy to compare the architecture of normal and neoplastic follicles and next genera- tion sequencing to analyze the T-cell receptor repertoire in FL lymph nodes (LN). Multiparameter analysis of LN showed that the proportion of T-follic- ular helper cells (TFH) in normal and neoplastic follicles is the same and that the previously reported increase in TFH numbers in FL is thus due to an increase in the number and not content of follicles. As in normal germinal centers, TFH were shown to have a close spatial correlation with proliferating B cells in neoplastic follicles, where features of immunological synapse for- mation were observed. The number of TFH in FL correlate with the rate of B- cell proliferation and TFH co-localized to activation induced cytidine deami- nase expressing proliferating B cells. T-cell receptor repertoire analysis of FL LN revealed that follicular areas are significantly more clonal when com- pared to the rest of the LN. These novel findings show that neoplastic folli- cles and germinal centers share important structural features and provide fur- ther evidence that TFH may play a role in driving B-cell proliferation and genomic evolution in TFH. Our results also suggest that targeting this interac- tion would be an attractive therapeutic option.
Introduction
Follicular lymphoma (FL) is a neoplasm of germinal center B cells that is usually characterized by the t(14;18) translocation and over-expression of BCL2.1,2 The clin- ical course is variable, prognosis is difficult to predict, and it is typically incurable.3,4 The tumor is infiltrated by numerous subsets of non-malignant T cells.5-8 Gene expression profiling (GEP) studies have shown that prognosis in FL can be correlat- ed with the signature of non-malignant T cells of the microenvironment rather than the tumor itself, indicating that the microenvironment is important in the patho- genesis of this disease.9,10 The relationship between FL B cells and their microenvi- ronment is complex; non-malignant T cells may either promote or inhibit tumor growth whilst the tumor itself can influence the composition of the microenviron- ment.11,12 Many groups have investigated the impact of microenvironment-related factors on outcome.10,13-16 These studies have, however, yielded contradictory
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1593-1603
Correspondence:
WILLIAM TOWNSEND
william.townsend@nhs.net
Received: March 4, 2019. Accepted: September 18, 2019. Pre-published: September 19, 2019.
doi:10.3324/haematol.2019.220160
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/106/6/1593
©2020 Ferrata Storti Foundation
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