Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape

Mangolini, Maurizio; Maiques-Díaz, Alba; Charalampopoulou, Stella; Gerhard-Hartmann, Elena; Bloehdorn, Johannes; Moore, Andrew R.; Giachetti, Giorgia; Lu, Junyan; Franklin, Valar Nila Roamio; Chilamakuri, Chandra Sekkar Reddy; Moutsopoulos, Ilias; Rosenwald, Andreas; Stilgenbauer, Stephan; Zenz, Thorsten; Mohorianu, Irina; D’Santos, Clive S.; Deaglio, Silvia; Hodson, Daniel J.; Martin-Subero, José Ignacio; Ringshausen, Ingo

doi:10.1038/s41467-022-33739-2

Cited by 13 publications

(16 citation statements)

References 77 publications

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“…Recently, results from Maurizio et al. suggested that Notch signalling could facilitate immune‐escape by upregulating PD‐L1 43 . Intriguingly, GEPIA database also indicated that Notch1 level significantly correlated PD‐L1 level in KIRC (Figure 7C).…”

Section: Resultsmentioning

confidence: 78%

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GHITM regulates malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling

Huang,

Liu,

et al. 2024

J Cellular Molecular Medi

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Growth hormone inducible transmembrane protein (GHITM), one member of Bax inhibitory protein‐like family, has been rarely studied, and the clinical importance and biological functions of GHITM in kidney renal clear cell carcinoma (KIRC) still remain unknown. In the present study, we found that GHITM was downregulated in KIRC. Aberrant GHITM downregulation related to clinicopathological feature and unfavourable prognosis of KIRC patients. GHITM overexpression inhibited KIRC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, GHITM overexpression could induce the downregulation of Notch1, which acts as an oncogene in KIRC. Overexpression of Notch1 effectively rescued the inhibitory effect induced by GHITM upregulation. More importantly, GHITM could regulate PD‐L1 protein abundance and ectopic overexpression of GHITM enhanced the antitumour efficiency of PD‐1 blockade in KIRC, which provided new insights into antitumour therapy. Furthermore, we also showed that YY1 could decrease GHITM level via binding to its promoter. Taken together, our study revealed that GHITM was a promising therapeutic target for KIRC, which could modulate malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling pathway.

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Section: Resultsmentioning

confidence: 78%

“…Recently, results from Maurizio et al suggested that Notch signalling could facilitate immune-escape by upregulating PD-L1 43. …”

mentioning

confidence: 99%

GHITM regulates malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling

Huang,

Liu,

et al. 2024

J Cellular Molecular Medi

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“…On the basis of our data, proliferation of CLL/MCL cells seems to be key for a successful and efficient gene editing. Moreover, using our cell coculture method, 10 we have shown a permanent protein depletion that is maintained in any offspring cell, enabling longer follow‐up downstream analyses and targeting of several candidate genes simultaneously.…”

Section: Figurementioning

confidence: 99%

“…While recently it has been demonstrated that it is possible to genetically manipulate nonactivated B cells, 9 the use of gene editing tools in malignant B cells is still elusive. Thus, to advance further in the genetic manipulation of primary malignant B cell, such as CLL and MCL, we took advantage of our cell culture system that allows the in vitro expansion of patient‐derived CLL/MCL cells for several weeks, regardless of the clinico‐biological subtype of the disease 10 . Using this cell culture system, in which primary cells are exposed to human CD40‐ligand, IL21, and BAFF secreted by murine stromal cells, we have now established a robust method for CRISPR‐Cas9 editing of patient‐derived malignant‐activated CLL/MCL cells.…”

Section: Figurementioning

confidence: 99%

Robust CRISPR-Cas9 Genetic Editing of Primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells

et al. 2023

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“…By secreting IFN-γ, CLL cells create an anti-apoptotic autocrine loop, and Notch upregulates both the cytokine and its receptor ( 106 ). Notch1-2 signaling represses genes fundamental to antigen-processing and presentation in CLL and mantel cell lymphoma cells, reducing their immunogenicity and having a negative impact on the prognosis of patients ( 107 ). The bivalent role of this pathway is re-emphasized by the fact that Notch2-DLL1 signaling is necessary in cytolytic CD8 T cell activation through perforin and granzyme B expression ( 108 ).…”

Section: Notch2 In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Role of Notch2 pathway in mature B cell malignancies

Mesini

Fiorcari²,

Atene³

et al. 2023

Front. Oncol.

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In recent decades, the Notch pathway has been characterized as a key regulatory signaling of cell-fate decisions evolutionarily conserved in many organisms and different tissues during lifespan. At the same time, many studies suggest a link between alterations of this signaling and tumor genesis or progression. In lymphopoiesis, the Notch pathway plays a fundamental role in the correct differentiation of T and B cells, but its deregulated activity leads to leukemic onset and evolution. Notch and its ligands Delta/Jagged exhibit a pivotal role in the crosstalk between leukemic cells and their environment. This review is focused in particular on Notch2 receptor activity. Members of Notch2 pathway have been reported to be mutated in Chronic Lymphocytic Leukemia (CLL), Splenic Marginal Zone Lymphoma (SMZL) and Nodal Marginal Zone Lymphoma (NMZL). CLL is a B cell malignancy in which leukemic clones establish supportive crosstalk with non-malignant cells of the tumor microenvironment to grow, survive, and resist even the new generation of drugs. SMZL and NMZL are indolent B cell neoplasms distinguished by a distinct pattern of dissemination. In SMZL leukemic cells affect mainly the spleen, bone marrow, and peripheral blood, while NMZL has a leading nodal distribution. Since Notch2 is involved in the commitment of leukemic cells to the marginal zone as a major regulator of B cell physiological differentiation, it is predominantly affected by the molecular lesions found in both SMZL and NMZL. In light of these findings, a better understanding of the Notch receptor family pathogenic role, in particular Notch2, is desirable because it is still incomplete, not only in the physiological development of B lymphocytes but also in leukemia progression and resistance. Several therapeutic strategies capable of interfering with Notch signaling, such as monoclonal antibodies, enzyme or complex inhibitors, are being analyzed. To avoid the unwanted multiple “on target” toxicity encountered during the systemic inhibition of Notch signaling, the study of an appropriate pharmaceutical formulation is a pressing need. This is why, to date, there are still no Notch-targeted therapies approved. An accurate analysis of the Notch pathway could be useful to drive the discovery of new therapeutic targets and the development of more effective therapies.

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Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape

Cited by 13 publications

References 77 publications

GHITM regulates malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling

GHITM regulates malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling

Robust CRISPR-Cas9 Genetic Editing of Primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells

Role of Notch2 pathway in mature B cell malignancies

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