Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy

Thomas Menter, Alexandar Tzankov, Emanuele Zucca, Eva Kimby, Magnus Hultdin, Christer Sundström, Klaus Beiske, Sergio Cogliatti, Yara Banz, Gieri Cathomas, Marja-Liisa Karjalainen-Lindsberg, Rainer Grobholz, Luca Mazzucchelli, Birgitta Sander, Hanne Hawle, Stefanie Hayoz, Stefan Dirnhofer, Thomas Menter, Alexandar Tzankov, Emanuele Zucca, Eva Kimby, Magnus Hultdin, Christer Sundström, Klaus Beiske, Sergio Cogliatti, Yara Banz, Gieri Cathomas, Marja-Liisa Karjalainen-Lindsberg, Rainer Grobholz, Luca Mazzucchelli, Birgitta Sander, Hanne Hawle, Stefanie Hayoz, Stefan Dirnhofer

Abstract

Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment-naïve FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P = 0·009) and increased amounts of PD1+ tumour-infiltrating T cells (P = 0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2 . In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression-free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents. [Correction added on 11 February 2020, after online publication: The NCT-trial number was previously incorrect and has been updated in this version].

Keywords: GATA3; PD1; follicular lymphoma; lenalidomide; rituximab.

© 2020 British Society for Haematology and John Wiley & Sons Ltd.

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