p53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1

Wang, Bei; Niu, Dong Xiao; Lai, Liyun; Ren, Ee Chee

doi:10.1038/ncomms3359

Cited by 128 publications

(126 citation statements)

References 33 publications

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“…Increased FAS expression with SGT-53 treatment could also increase CTL-mediated apoptosis of tumor cells since CTLs use FAS/FAS ligand binding to induce apoptosis of target cells during the CTL-tumor cell interaction. 36,37 These observations recapitulate previous findings, 20,21,38–40 and it is reasonable to believe that elevated expression of these component of immunogenicity would be instrumental in achieving efficient anti-tumor immune responses.…”

Section: Discussionsupporting

confidence: 86%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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Section: Discussionsupporting

confidence: 86%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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“…Another link between p53 and DC function is the reported ability of p53 to enhance the expression of MHC class I molecules (Figure 2) 135, 136 . It is likely that this would enhance the induction of cytotoxic CD8+ T cells that are specific for viruses or other intracellular pathogens, and it will be interesting to assess whether p53 signalling plays a direct role in DC antigen presentation.…”

Section: P53 Functions In Innate and Adaptive Immunitymentioning

confidence: 99%

Emerging roles of p53 and other tumour-suppressor genes in immune regulation

et al. 2016

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Tumour-suppressor genes are indispensable for the maintenance of genomic integrity. Recently, several of these genes, including p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour-suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-suppressor genes in tumour immunology as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease, and facilitate the development of more effective immunotherapies. Consequently, tumour-suppressor genes are emerging as potential guardians of immune integrity.

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“…Increasing evidence indicates that p53 also plays crucial roles in the regulation of immune responses, specifically in several aspects of the cytotoxic T-lymphocyte (CTL)-tumor cell interaction (5–8). Indeed, p53 responsive elements have been found in genes which impact the CTL response including the transporter associated with antigen processing 1 (TAP1) and endoplasmic reticulum amino peptidase 1 (ERAP1), through which p53 is directly involved in the upregulation of antigen presentation via the major histocompatibility complex (MHC) I pathway (5, 7) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, p53 responsive elements have been found in genes which impact the CTL response including the transporter associated with antigen processing 1 (TAP1) and endoplasmic reticulum amino peptidase 1 (ERAP1), through which p53 is directly involved in the upregulation of antigen presentation via the major histocompatibility complex (MHC) I pathway (5, 7) (Figure 1). The interaction between MHC I on cancer cells and the T-cell receptor (TCR) on CTLs is essential for the adaptive immune response to cancer; however, proper co-stimulation is also necessary for the CTL-mediated tumor cell killing (9).…”

Section: Introductionmentioning

confidence: 99%

Regulation of cytotoxic T-cell responses by p53 in cancer

Braun

Iwakuma

2016

Transl. Cancer Res.

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An intriguing aspect of the tumor suppressor p53 is its ability to communicate to the adaptive immune system and control the cytotoxic T-lymphocyte (CTL) response to cancer cells. Wild-type p53 (wtp53) communicates with CTLs through proteins involved in the major histocompatibility complex (MHC) class I antigen presentation pathway [e.g., transporter associated with antigen processing 1 (TAP1) and endoplasmic reticulum amino peptidase 1 (ERAP1)], the apoptosis signal receptor Fas/APO-1, and the inhibitory immune-checkpoint programmed death-ligand 1 (PD-L1). The presence of wtp53 in cancer cells ultimately promotes effector CTL-induced tumor cell death. Analogously, wtp53 in tumors unleashes the CTL response via inhibition of PD-L1 and enhances their effectiveness by upregulating Fas/APO-1 and MHC I. Given that p53 is mutated in approximately 50% of human cancers and also impacts the immunoreactivity of cancer cells, a significant number of patients can be affected by the impaired CTL response that results from non-functional p53. An attenuated CTL response due to p53 mutations could decrease response rates to immunotherapeutic drugs, leading to poor patient prognoses. This review article will summarize how p53 can regulate the cell-mediated adaptive immune response to cancer.

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p53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1

Cited by 128 publications

References 33 publications

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Emerging roles of p53 and other tumour-suppressor genes in immune regulation

Regulation of cytotoxic T-cell responses by p53 in cancer

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