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Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing.

ABSTRACT: Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach toward combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity, and the suppression of tumor immunoevasion. To date, the ex vivo re-engineering of immune cells directed to inhibit the expression of immune checkpoints or to express synthetic immune receptors (chimeric antigen receptor therapy) has shown success in some settings, such as in the treatment of melanoma, lymphoma, liver, and lung cancer. However, advancements in nuclease-deactivated CRISPR-associated nuclease-9 (dCas9)-mediated transcriptional activation or repression and Cas13-directed gene suppression present novel avenues for the development of tumor immunotherapies. In this review, the basis for development, mechanism of action, and outcomes from recently published Cas9-based clinical trial (genetic editing) and dCas9/Cas13-based pre-clinical (epigenetic editing) data are discussed. Lastly, we review cancer immunotherapy-specific considerations and barriers surrounding use of these approaches in the clinic.

SUBMITTER: Alves E

PROVIDER: S-EPMC8142043 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing.

Alves Eric E Taifour Shahama S Dolcetti Riccardo R Chee Jonathan J Nowak Anna K AK Gaudieri Silvana S Blancafort Pilar P

Molecular therapy. Methods & clinical development 20210424

Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach toward combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity, and the suppression of tumor immunoevasion. To date, the <i>ex vivo</i> re-engineering of immune ...[more]

PMID: 34095343

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Project description:Background: Tumor associated macrophages (TAMs) have strong plasticity and if reprogrammed, can clear tumor cells and regulate the adaptive immune system for cancer immunotherapy. Deubiquitinating enzymes (DUBs), which can remove ubiquitin (Ub) from Ub-modified substrates, have been associated with oncogenic metabolism but are not well-known for regulating TAMs repolarization. Methods: The expression of DUB related genes in macrophages (MΦs) was detected by reverse transcription-PCR. Flow cytometry and immunofluorescence were used to detect the changes of immune cells in the tumor microenvironment and spleen, including M1 (CD11b+F4/80+CD86+CD206-), and M2 (CD11b+F4/80+CD86-CD206+) MΦs, and IFN-γ+CD8+T cells. A proliferation assay was used to determine the effect of M2 MΦs treated with a USP7 inhibitor on T cell proliferation. Western blotting was used to detect the expression of USP7 and the activation of the MAPK pathway. The TGCA database was used to assess the role of USP7 in the immune microenvironment of human lung adenocarcinoma (LUAD). Results: 51 DUB genes were screened and USP7 was identified as a highly expressed gene in M2 but not M1 MΦs. Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 MΦs, favoring CD8+T cells proliferation in vitro. USP7 inhibitors delayed tumor growth in mice with Lewis lung carcinoma, and promoted tumor infiltration of M1 MΦs and IFN-γ+CD8+T cells. Depletion of TAMs attenuated these therapeutic effects. USP7 inhibition was shown to mediate MΦs reprogramming by activating the p38 MAPK pathway. Administration of USP7 inhibitors increased the expression of programmed cell death ligand 1 (PD-L1) in tumors, while blocking programmed cell death protein 1 (PD-1) provided an effective anti-tumor response. Clinical databases suggest that high expression of USP7 in LUAD was negatively correlated with innate and adaptive immunity. Conclusions: Taken together, these results provide evidence to suggest that therapeutic approaches targeting USP7, in combination with immunotherapy, should be considered for lung cancer treatment.

Project description:Curative management of pancreatic adenocarcinoma is limited because this malignancy remains resistant to most chemotherapeutic drugs. Strategies that reverse epigenetic alterations offer a unique opportunity for cancer cell reprogramming, which is valuable for development of new treatments. The aim of this work was to reprogram pancreatic ductal adenocarcinoma (PDAC) cells toward a less aggressive and drug-responsive phenotype. The process applied is called "epigenetic reprogramming". To evaluate the efficiency of PDAC epigenetic reprogramming, we assessed tumor growth and drug response in PANC-1 cells after exposure to non-cytotoxic doses of the demethylating agent 5-azacytidine (5-AZA). Here, we showed that an epigenetic regimen using 5-AZA promoted an anti-cancer response by inhibiting PDAC tumor growth in vivo after the engraftment of treated cells. Remarkably, the subsequent addition of gemcitabine (GEM) to the 5-AZA-mediated reprogramming resulted in a marked growth inhibition effect in GEM-resistant pancreatic cancer cells. We observed that various characteristic peptides expressed in the pancreas, which included the antiproliferative hormone somatostatin (SST) and the SST receptor 2 (SSTR2), were significantly upregulated in the epigenetically reprogrammed PDAC cells. The inhibitory effect of octreotide (OCT), an SST analog, was tested on PDAC cells and found to be improved after cell reprogramming. Furthermore, we found that SST gene expression restoration following 5-AZA treatment or following knockdown of the DNA methyltransferase (DNMT) 1 enzyme was associated with the reversion of SST epigenetic silencing through regional CpG demethylation. Lastly, we confirmed the efficacy of 5-AZA-based epigenetic reprogramming in vivo using a PDAC tumor growth model. In conclusion, this study demonstrates that epigenetic reprogramming using the demethylating compound 5-AZA shows anti-cancer effects in PANC-1 cells and is potentially attractive for the treatment of solid tumors.

Dataset Information

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing.

Publications

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing.

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