Stimulation of an anti-tumor immune response with "chromatin-damaging" therapy.
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.
['Chen|Minhui|M|', 'Brackett|Craig M|CM|', 'Burdelya|Lyudmila G|LG|', 'Punnanitinont|Achamaporn|A|', 'Patnaik|Santosh K|SK|', 'Matsuzaki|Junko|J|', 'Odunsi|Adekunle O|AO|', 'Gudkov|Andrei V|AV|', 'Singh|Anurag K|AK|', 'Repasky|Elizabeth A|EA|http://orcid.org/0000-0002-9554-4152', 'Gurova|Katerina V|KV|http://orcid.org/0000-0001-9189-0712']
D000818:Animals D017209:Apoptosis D002227:Carbazoles D049109:Cell Proliferation D018925:Chemokines D002843:Chromatin D003110:Colonic Neoplasms D016207:Cytokines D005260:Female D006801:Humans D007109:Immunity D051379:Mice D008807:Mice, Inbred BALB C D016513:Mice, SCID D014407:Tumor Cells, Cultured D023041:Xenograft Model Antitumor Assays
Curaxin Histone Chromatin damage CBL0137 Tumor cell immunogenicity T cells