Stimulation of an anti-tumor immune response with "chromatin-damaging" therapy.
Minhui ChenCraig M BrackettLyudmila G BurdelyaAchamaporn PunnanitinontSantosh K PatnaikJunko MatsuzakiAdekunle O OdunsiAndrei V GudkovAnurag K SinghElizabeth A RepaskyKaterina V GurovaPublished in: Cancer immunology, immunotherapy : CII (2021)
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.
Keyphrases
- dendritic cells
- immune response
- genome wide
- gene expression
- dna damage
- transcription factor
- high fat diet induced
- nk cells
- dna methylation
- type diabetes
- bone marrow
- single cell
- oxidative stress
- cell free
- insulin resistance
- single molecule
- type iii
- genome wide identification
- newly diagnosed
- cell migration
- bioinformatics analysis
- nucleic acid
- artificial intelligence
- long non coding rna
- amino acid