Cancer-Specific Loss of p53 Leads to a Modulation of Myeloid and T Cell Responses

Blagih, Julianna; Zani, Fabio; Chakravarty, Probir; Hennequart, Marc; Pilley, Steven E.; Hobor, Sebastijan; Höck, A.; Walton, Josephine; Morton, Jennifer P.; Grönroos, Eva; Mason, Susan; Yang, Ming; McNeish, Iain A.; Swanton, Charles; Blyth, Karen; Vousden, Karen H.

doi:10.1016/j.celrep.2019.12.028

Cited by 110 publications

(90 citation statements)

References 76 publications

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“…In addition to modifying CSF1 signalling, several other p53-associated pathways influence macrophage recruitment and function. For example, myeloid cells within p53-null tumours are recruited and reprogrammed through the secretome of p53-deficient cancer cells towards tumour-promoting macrophages (Blagih et al, 2020). Furthermore, some mutant forms of p53 gain the ability to influence macrophage behaviour.…”

Section: Regulation Of Immunomodulatory Ligands By Wild-type and Mutamentioning

confidence: 99%

“…3). In addition to acquiring more Tregs, p53-null tumour-bearing mice develop highly suppressive Treg populations in comparison to wild-type controls (Blagih et al, 2020). Another consequence of p53 loss within tumours is a reduction of activated inflammatory cytokineproducing T cells, which are involved in tumour regression.…”

Section: Regulation Of Immunomodulatory Ligands By Wild-type and Mutamentioning

confidence: 99%

“…Another consequence of p53 loss within tumours is a reduction of activated inflammatory cytokineproducing T cells, which are involved in tumour regression. This ability of p53-null cancer cells to promote immune suppression can be overcome by Treg depletion and CSF1R neutralization (Blagih et al, 2020), highlighting a complex interplay of both suppressive myeloid and Treg populations in dampening T cell effector function.…”

Section: Regulation Of Immunomodulatory Ligands By Wild-type and Mutamentioning

confidence: 99%

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p53, cancer and the immune response

Blagih

Buck

Vousden

2020

Journal of Cell Science

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210

137

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The importance of cancer-cell-autonomous functions of the tumour suppressor p53 (encoded by TP53) has been established in many studies, but it is now clear that the p53 status of the cancer cell also has a profound impact on the immune response. Loss or mutation of p53 in cancers can affect the recruitment and activity of myeloid and T cells, allowing immune evasion and promoting cancer progression. p53 can also function in immune cells, resulting in various outcomes that can impede or support tumour development. Understanding the role of p53 in tumour and immune cells will help in the development of therapeutic approaches that can harness the differential p53 status of cancers compared with most normal tissue.

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Section: Regulation Of Immunomodulatory Ligands By Wild-type and Mutamentioning

confidence: 99%

Section: Regulation Of Immunomodulatory Ligands By Wild-type and Mutamentioning

confidence: 99%

Section: Regulation Of Immunomodulatory Ligands By Wild-type and Mutamentioning

confidence: 99%

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p53, cancer and the immune response

Blagih

Buck

Vousden

2020

Journal of Cell Science

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210

137

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“…To further evaluate the anti-tumor effect of PTX NPs, we excised the liver, kidney, and tumor tissues for pathology and measurement of p53 protein levels. 33…”

Section: Antitumor Activitymentioning

confidence: 99%

<p>Targeted Prodrug-Based Self-Assembled Nanoparticles for Cancer Therapy</p>

Wang¹,

Fan²,

Zhu³

et al. 2020

IJN

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Background: Targeted prodrug has various applications as drug formulation for tumor therapy. Therefore, amphoteric small-molecule prodrug combined with nanoscale characteristics for the self-assembly of the nano-drug delivery system (DDS) is a highly interesting research topic. Methods and Results: In this study, we developed a prodrug self-assembled nanoplatform, 2-glucosamine-fluorescein-5(6)-isothiocyanate-glutamic acid-paclitaxel (2DA-FITC-PTX NPs) by integration of targeted small molecule and nano-DDS with regular structure and perfect targeting ability. 2-glucosamine (DA) and paclitaxel were conjugated as the targeted ligand and anti-tumor chemotherapy drug by amino acid group. 2-DA molecular structure can enhance the targeting ability of prodrug-based 2DA-FITC-PTX NPs and prolong retention time, thereby reducing the toxicity of normal cell/tissue. The fluorescent dye FITC or near-infrared fluorescent dye ICG in prodrug-based DDS was attractive for in vivo optical imaging to study the behavior of 2DA-FITC-PTX NPs. In vitro and in vivo results proved that 2DA-FITC-PTX NPs exhibited excellent targeting ability, anticancer activity, and weak side effects. Conclusion: This work demonstrates a new combination of nanomaterials for chemotherapy and may promote prodrug-based DDS clinical applications in the future.

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“…Studies in mice have shown that TP53 inactivation in murine T cells augments differentiation to T helper type (Th)17 cells, thereby promoting spontaneous autoimmunity (16), and in contrast, active TP53 can suppress inflammatory responses through the inhibition of tumor necrosis factor (TNF) transcription (17). Cancer-specific loss of TP53 expression in lung and pancreas tumor models protects from immune-mediated elimination through the recruitment of both myeloid cells and regulatory T (Treg) cells (18). In human tumors, TP53 mutations are enriched in the immune favorable, Th1-dominant phenotype of breast cancer, which expresses high levels of negative immune checkpoints programmed death receptor ligand 1 (PD-L1) and programmed death receptor 1 (PD1), as well as immune suppressive mediators such as indoleamine 2,3-dioxygenase-1 (19).…”

Section: Introductionmentioning

confidence: 99%

TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

Lai

Vadakekolathu

Reeder

et al. 2020

Preprint

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Purpose: Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53 mutated AML and to determine whether TP53 abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches. Experimental Design: The NanoString Pan-Cancer IO 360™ assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults with TP53 mutated AML (n=42) or TP53 wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (11 cases with TP53 mutations and/or 17p deletion with genomic loss of TP53) who received immunotherapy with flotetuzumab, an investigational CD123×CD3 bispecific DART ® molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort and a Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) cohort. Results: All TCGA cases with TP53 mutations (n=13) expressed higher levels of negative immune checkpoints, inflammatory chemokines, interferon (IFN)-γ-inducible molecules, and had a higher tumor inflammation signature (TIS) score, compared with TCGA cases with other riskdefining molecular lesions. The comparison between TP53 mutated and TP53 wild type primary BM samples showed higher expression of IFNG, FoxP3, immune checkpoints and markers of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival. In vitro modeling experiments with AML cell lines showed heightened expression of IFN-γ and inflammation pathway genes in KG-1 cells (loss-of-function mutation of TP53) compared with Kasumi-1 cells (gain-of-function mutation of TP53). Finally, 5 out of 11 (45.5%) patients with R/R AML and TP53 abnormalities showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS, FoxP3, CD8 T-cell abundance, inflammatory chemokine and PD1 gene expression scores at baseline compared with non-responders. Conclusions:This study provides evidence for a correlation between IFN-γ-dominant immune subtypes and TP53 abnormalities. The anti-leukemic activity with flotetuzumab encourages further study of this immunotherapeutic approach in this patient subgroup.further studies of T-cell targeting immunotherapeutic approaches in patients with TP53 mutations.

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Cancer-Specific Loss of p53 Leads to a Modulation of Myeloid and T Cell Responses

Cited by 110 publications

References 76 publications

p53, cancer and the immune response

p53, cancer and the immune response

<p>Targeted Prodrug-Based Self-Assembled Nanoparticles for Cancer Therapy</p>

TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

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