Molecular Signatures Implicate Innate Immune Cells, Fibrosis, and Angiogenesis in Survival Following R-CHOP Treatment of Diffuse Large B Cell Lymphoma
Authors: Lenz Georg , Wright George , Dave Sandeep , Xiao Wenming , Powell John , Zhao Hong , Xu Weihong , Tan Bruce , Goldschmidt Neta , Iqbal Javeed , Vose Julie , Bast Martin A , Fu Kai , Weisenburger Dennis D. , Greiner Timothy C. , Armitage James O. , Kyle Alastair , May Lorraine , Gascoyne Randy D. , Connors Joseph M. , Troen Gunhild , Holte Harald , Kvaloy Stein , Dierickx Daan , Verhoef Gregor , Delabie Jan , Smeland Erlend B. , Jares Pedro , Martinez Antonio , Lopez-Guillermo Armando , Montserrat Emili , Campo Elias , Braziel Rita M. , Miller Thomas P. , Rimsza Lisa M. , Cook James R. , Pohlman Brad , Sweetenham John William , Tubbs Raymond R. , Fisher Richard I. , Hartmann Elena , Rosenwald Andreas , Ott German , Muller-Hermelink Hans- Konrad , Wrench David , Lister T. Andrew , Jaffe Elaine S. , Wilson Wyndham , Chan Wing C. , Staudt Louis M. 
Published: April 2020

Abstract
Background: The addition of Rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the overall survival of patients with diffuse large B cell lymphoma (DLBCL) by 10–15%. To evaluate the biological basis of survival for DLBCL, we profiled gene expression in biopsy samples from patients treated with R-CHOP.
Methods: Whole genome Affymetrix U133 2.0 plus arrays were used to profile gene expression in pre-treatment biopsies from patients with de novo DLBCL who received CHOP (n=181) or R-CHOP (n=233). Samples were classified as germinal center B cell-like (GCB), activated B cell-like (ABC) or unclassified DLBCL. A multivariate gene expression-based survival predictor was created using CHOP cases as training and R-CHOP cases as validation set.
Results: R-CHOP treated patients with GCB DLBCL had a more favorable survival than those with ABC DLBCL, with 3-year overall survival rates of 84% and 56%, respectively (p&lt;0.001). A multivariate model created from 3 gene expression signatures – termed “germinal center B cell”, “stromal-1”, and “stromal-2” – predicted survival in both CHOP and R-CHOP cases, defining quartile groups among R-CHOP-treated patients with 3-year overall survival rates of 89%, 82%, 74%, and 48% (p&lt;0.001), and 3-year progression-free survival rates of 84%, 69%, 61% and 33% (p&lt;0.001). The germinal center B cell signature genes were more highly expressed in the malignant cells, whereas the stromal-1 and stromal-2 signature genes were more highly expressed in the non-malignant cells. The stromal-1 signature was associated with favorable outcome when expressed, and reflected extracellular matrix deposition and infiltration by histiocytic innate immune cells. In contrast, the prognostically unfavorable stromal-2 signature reflected angiogenesis and tumor blood vessel density.
Conclusion: Survival in DLBCL is critically influenced by the composition of the tumor microenvironment, suggesting that therapeutic interference with microenvironmental interactions might further improve outcome in DLBCL. Specifically, inhibition of angiogenesis may be beneficial for a subset of patients with high relative expression of the stromal-2 signature and increased tumor blood vessel density.