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

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 and Sergio Roa

Key Points

  • Constitutive NF-κB activation and blocked terminal differentiation trigger p53 signaling and antitumor immune escape mechanisms in ABC-DLBCL.

  • Simultaneous PD-1 blockade improves long-term efficacy of anti-CD20 immunotherapy in a multilesion preclinical mouse model of ABC-DLBCL.

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.

  • Submitted December 10, 2018.
  • Accepted April 4, 2019.
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