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Blood. 2019 Apr 11. pii: blood.2018889931. doi: 10.1182/blood.2018889931. [Epub ahead of print]

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

Author information

1
Oncohematology, Centro de Investigacion Medica Alplicada. Universidad de Navarra., Spain.
2
CIMA Universidad de Navarra.
3
Oncology, CIMA, Spain.
4
CIMA NAVARRA UNIVERSITY, Spain.
5
Clinica Universidad de Navarra, Spain.
6
Centre for Applied Medical Research, Spain.
7
Unidad de Citometria de Flujo, Centro de Investigacion Medica Alplicada. Universidad de Navarra., Spain.
8
CIMA Navarra Universisty, Spain.
9
Weill Cornell Medicine, United States.
10
Stony Brook University.
11
University Hospitals Leuven, Belgium.
12
Department od Experimental Medicine, University of Genoa, Italy.
13
Center for Applied Medical Research (CIMA), Spain.
14
University of Salamanca.
15
University of Navarra, Pamplona, Spain.
16
CIMA Universidad de Navarra, Spain.
17
Center for Applied Medical Research, CIMA, Spain.
18
Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, CIMA, Spain.
19
Stony Brook University, United States.
20
Department of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, United States.
21
Hematological Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Spain.
22
Hemato-Oncology, Center for Applied Medical Research (CIMA) University of Navarra, Spain sroa@unav.es.

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.

PMID:
30975638
DOI:
10.1182/blood.2018889931

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