Scientific publications

PD-1/PD-L1 immune checkpoint and p53 loss facilitate tumor progression in activated B-cell diffuse large B-cell lymphomas

May 30, 2019 | Magazine: Blood

Marién Pascual, María Mena-Varas, Eloy Francisco Robles, Maria-Jose Garcia-Barchino, Carlos Panizo, Sandra Hervas-Stubbs, Diego Alignani, Ainara Sagardoy, Jose Ignacio Martinez-Ferrandis, Karen L Bunting, Stephen Meier, Xavier Sagaert, Davide Bagnara, Elizabeth Guruceaga, Oscar Blanco, Jon Celay, Alvaro Martínez-Baztan, Noelia Casares, Juan José Lasarte, Thomas MacCarthy, Ari Melnick, Jose Angel Martinez-Climent, Sergio Roa


Abstract

Refractory or relapsed diffuse large B-cell lymphoma (DLBCL) often associates with the activated B-cell-like (ABC) subtype and genetic alterations that drive constitutive NF-κB activation and impair B-cell terminal differentiation. Here, we show that DNA damage response by p53 is a central mechanism suppressing the pathogenic cooperation of IKK2ca-enforced canonical NF-κB and impaired differentiation resulting from Blimp1 loss in ABC-DLBCL lymphomagenesis.

We provide evidences that the interplay between these genetic alterations and the tumor microenvironment select for additional molecular addictions that promote lymphoma progression, including aberrant coexpression of FOXP1 and the B-cell mutagenic enzyme activation-induced deaminase, and immune evasion through major histocompatibility complex class II downregulation, PD-L1 upregulation, and T-cell exhaustion.

Consistently, PD-1 blockade cooperated with anti-CD20-mediated B-cell cytotoxicity, promoting extended T-cell reactivation and antitumor specificity that improved long-term overall survival in mice. Our data support a pathogenic cooperation among NF-κB-driven prosurvival, genetic instability, and immune evasion mechanisms in DLBCL and provide preclinical proof of concept for including PD-1/PD-L1 blockade in combinatorial immunotherapy for ABC-DLBCL.

CITATION  Blood. 2019 May 30;133(22):2401-2412. doi: 10.1182/blood.2018889931. Epub 2019 Apr 11.

Our authors

María José García Barchino
Dr. Sandra Hervás Stubbs
Researcher | Principal Investigator Immunology and Immunotherapy Research Program
Diego Alignani
Laboratory technician Cytometry Platform
Elizabet Guruceaga Martínez
Bioinformatics Research Technician Bioinformatics Platform
Dr. Jon Celay Leoz