Dataset Information

Stimulation of an anti-tumor immune response with "chromatin-damaging" therapy.

ABSTRACT: Curaxins are small molecules that bind genomic DNA and interfere with DNA-histone interactions leading to the loss of histones and decondensation of chromatin. We named this phenomenon 'chromatin damage'. Curaxins demonstrated anti-cancer activity in multiple pre-clinical tumor models. Here, we present data which reveals, for the first time, a role for the immune system in the anti-cancer effects of curaxins. Using the lead curaxin, CBL0137, we observed elevated expression of several group of genes in CBL0137-treated tumor cells including interferon sensitive genes, MHC molecules, some embryo-specific antigens suggesting that CBL0137 increases tumor cell immunogenicity and improves recognition of tumor cells by the immune system. In support of this, we found that the anti-tumor activity of CBL0137 was reduced in immune deficient SCID mice when compared to immune competent mice. Anti-tumor activity of CBL0137 was abrogated in CD8⁺ T cell depleted mice but only partially lost when natural killer or CD4⁺ T cells were depleted. Further support for a key role for the immune system in the anti-tumor activity of CBL0137 is evidenced by an increased antigen-specific effector CD8⁺ T cell and NK cell response, and an increased ratio of effector T cells to Tregs in the tumor and spleen. CBL0137 also elevated the number of CXCR3-expressing CTLs in the tumor and the level of interferon-γ-inducible protein 10 (IP-10) in serum, suggesting IP-10/CXCR3 controls CBL0137-elicited recruitment of effector CTLs to tumors. Our collective data underscores a previously unrecognized role for both innate and adaptive immunity in the anti-tumor activity of curaxins.

SUBMITTER: Chen M

PROVIDER: S-EPMC8726059 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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 (M?s) 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+) M?s, and IFN-?+CD8+T cells. A proliferation assay was used to determine the effect of M2 M?s 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 M?s. Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 M?s, favoring CD8+T cells proliferation in vitro. USP7 inhibitors delayed tumor growth in mice with Lewis lung carcinoma, and promoted tumor infiltration of M1 M?s and IFN-?+CD8+T cells. Depletion of TAMs attenuated these therapeutic effects. USP7 inhibition was shown to mediate M?s 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.

Dataset Information

Stimulation of an anti-tumor immune response with "chromatin-damaging" therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets