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Spatial Signatures Identify Immune Escape via PD-1 as a Defining Feature of T-cell/Histiocyte-rich Large B-cell Lymphoma

Authors: Griffin, Gabriel K.; Weirather, Jason L.; Roemer, Margaretha; Lipschitz, Mikel; Kelley, Alyssa; Chen, Pei-Hsuan; Gusenleitner, Daniel; Jeter, Erin; Gjini, Evisa; Chapuy, Bjoern; Rosenthal, Michael; Xu, Jie; Chen, Benjamin J; Sohani, Aliyah; Lovitch, Scott B.; Abramson, Jeremy; Ishizuka, Jeffrey Joseph; Kim, Austin I; Jacobson, Caron A.; LaCasce, Ann S.; Fletcher, Christopher D.M.; Neuberg, Donna; Freeman, Gordon J; Hodi, F Stephen; Wright, Kyle; Ligon, Azra H; Jacobsen, Eric D.; Armand, Philippe; Shipp, Margaret A.; Rodig, Scott J.

Online: https://ashpublications.org/blood/article/doi/10.1182/blood.2020006464/463601/Spatial-Signatures-Identify-Immune-Escape-via-PD1

Issue: Blood . 2021 Mar 11;137(10):1353-1364.


T-cell/histiocyte-rich large B cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbor PD-L1/PD-L2 copy gain or amplification in 64% of cases, which is associated with increased PD-L1 expression (p = 0.0111). By directed and unsupervised spatial analyses of multi-parametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune ‘neighborhoods’ in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1-positive T cells. Further, unbiased clustering of spatially-resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in three of five patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies, including two complete responses and one partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL, and also support the potential utility of spatially-resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.