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

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.

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

“…In DLBCL, patients with high expression of PD-1/PDL1 on T cells and macrophages had significantly poorer survival after R-CHOP (Xu-Monette et al, 2019). In this context, and in line with our data, it has been recently shown that loss of TP53 21 increases PD-L1 in a murine lymphoma model of DLBCL, inducing immune evasion, which could be overcome with PD1-blockade (Pascual et al, 2019).…”

H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients

“…By introducing a primary transgenic lymphoma model with defined genetic lesions to interrogate distinct biologies—as presented here for the Suv39h1-dependent induction of cellular senescence in response to therapy—followed by the exploration of a genetically unbiased clinical trial-like mouse lymphoma cohort, all in a syngeneic, immune-competent context, we provide a DLBCL-approximated test platform for functional investigations. While a large body of literature underscores the successful exploration of functional lymphoma features in Eµ- myc mice and the subsequent validation of these findings in human DLBCL 23 , 27 , 28 , 40 , 54 – 56 , we certainly acknowledge limitations of this transgenic model as a reflection of DLBCL pathogenesis, particularly in light of numerous mouse models developed to more faithfully recapitulate GCB- or ABC-subtype features of human DLBCL 57 – 68 . However, while those models elegantly provide examples for distinct routes into GCB- or ABC-skewed diffuse large B-cell lymphomagenesis, they are, in turn, selectively composed of complexity-reduced genetics out of the overwhelming heterogeneity human DLBCL exhibit as a cardinal property.…”

“…f Circular workflow of functional interrogations in mouse models of cancer harboring defined genetic lesions, investigation of genetically unmanipulated mouse tumors in a clinical trial-like setting in vivo, and cross-species application of the genetic determinants of novel biological functions and intervention-evoked dynamic state switches learned therein in corresponding human cancer patient cohorts. exploration of functional lymphoma features in Eµ-myc mice and the subsequent validation of these findings in human DLBCL 23,27,28,40,[54][55][56] , we certainly acknowledge limitations of this transgenic model as a reflection of DLBCL pathogenesis, particularly in light of numerous mouse models developed to more faithfully recapitulate GCB-or ABC-subtype features of human DLBCL [57][58][59][60][61][62][63][64][65][66][67][68] . However, while those models elegantly provide examples for distinct routes into GCB-or ABC-skewed diffuse large B-cell lymphomagenesis, they are, in turn, selectively composed of complexity-reduced genetics out of the overwhelming heterogeneity human DLBCL exhibit as a cardinal property.…”

ZNF143 Suppresses Cell Apoptosis and Promotes Proliferation in Gastric Cancer via ROS/p53 Axis

“…Convincing evidence shows that excessive ROS production exceeds cellular antioxidant defenses, trig-gering apoptosis. The p53 gene is known as the guardian of the genome and is capable of activating cell cycle, DNA repair, and apoptosis to maintain the stability of the cell genome [28]. Bcl-2 and Bax are very important to apoptosis.…”