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.Copyright © 2020 American Society of Hematology.
About The Expert
Gabriel K Griffin
Jason L Weirather
Margaretha Roemer
Mikel Lipschitz
Alyssa Kelley
Pei-Hsuan Chen
Daniel Gusenleitner
Erin Jeter
Evisa Gjini
Bjoern Chapuy
Michael Rosenthal
Jie Xu
Benjamin J Chen
Aliyah Sohani
Scott B Lovitch
Jeremy Abramson
Jeffrey Joseph Ishizuka
Austin I Kim
Caron A Jacobson
Ann S LaCasce
Christopher D M Fletcher
Donna Neuberg
Gordon J Freeman
F Stephen Hodi
Kyle Wright
Azra H Ligon
Eric D Jacobsen
Philippe Armand
Margaret A Shipp
Scott J Rodig
References
PubMed