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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, José Ignacio Martínez, 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-kB 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 multi-lesion 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-kB 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-kB and impaired differentiation due to Blimp1 loss in ABC-DLBCL lymphomagenesis. We provide evidences that the interplay between these genetic alterations and the tumor microenvironment (TME) select for additional molecular addictions that promote lymphoma progression, including aberrant co-expression of FOXP1 and the B-cell mutagenic enzyme AID, and immune evasion through MHC-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 anti-tumor specificity that improved long-term overall survival in mice. Our data support a pathogenic cooperation between NF-kB-driven pro-survival, genetic instability and immune evasion mechanisms in DLBCL, and provide pre-clinical proof-of-concept for including PD-1/PD-L1 blockade in combinatorial immunotherapy for ABC-DLBCL.

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