TitlePD-1/PD-L1 immune checkpoint and p53 loss facilitate tumor progression in activated B-cell diffuse large B-cell lymphomas.
Publication TypeJournal Article
Year of Publication2019
AuthorsPascual, Marien, Mena-Varas Maria, Robles Eloy Francisco, Garcia-Barchino Maria-Jose, Panizo Carlos, Hervas-Stubbs Sandra, Alignani Diego, Sagardoy Ainara, Martinez-Ferrandis Jose Ignacio, Bunting Karen L., Meier Stephen, Sagaert Xavier, Bagnara Davide, Guruceaga Elizabeth, Blanco Oscar, Celay Jon, Martínez-Baztan Alvaro, Casares Noelia, Lasarte Juan José, MacCarthy Thomas, Melnick Ari, Martínez-Climent Jose Angel, and Roa Sergio
Date Published2019 May 30
KeywordsAnimals, B-Lymphocytes, B7-H1 Antigen, Female, Gene Expression Regulation, Neoplastic, Humans, Immunotherapy, Lymphocyte Activation, Lymphoma, Large B-Cell, Diffuse, Male, Mice, Mice, Transgenic, Programmed Cell Death 1 Receptor, T-Lymphocytes, Tumor Escape, Tumor Suppressor Protein p53

<p>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.</p>

Alternate JournalBlood
PubMed ID30975638
PubMed Central IDPMC6543517
Grant ListR01 AI132507 / AI / NIAID NIH HHS / United States
R01 CA187492 / CA / NCI NIH HHS / United States
R01 GM111741 / GM / NIGMS NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States