DNA methyltransferase inhibition promotes recruitment of myeloid-derived suppressor cells to the tumor microenvironment through induction of tumor cell-intrinsic interleukin-1.

DNA methyltransferase (DNMT) inhibitors are used for treatment of certain hematological malignancies and exert anti-cancer activity through diverse mechanisms, including reexpression of tumor suppressor genes and anti-viral responses triggered by expression of endogenous retroviruses. Despite advances in the pharmacokinetic properties of DNMT inhibitors, the efficacy of these drugs in solid cancers remains low. Here, we show in cell lines and clinical and experimental tumors across multiple cancer types that DNMT inhibition induces the expression of interleukin-1 (IL-1), a cytokine with proinflammatory and protumorigenic properties. Specifically, this tumor-intrinsic IL-1 expression modulates the chemokine landscape of tumors and leads to the recruitment of monocytic myeloid-derived suppressor cells to the tumor microenvironment, processes that can be blocked by IL-1 antagonists. Molecular analysis demonstrates complex patterns of IL-1 and interferon activation and crosstalk in response to DNMT inhibition, which depend on the integrity of IRF- and NF-κB-mediated antiviral pathways and may determine the outcome of DNMT-inhibitor treatment. Together, our results show that DNMT inhibitors may negatively affect the microenvironment of a large subset of tumors and suggest that co-treatment with IL-1 antagonists may be a favorable combination for these patients.

Preparation and Evaluation of [18F]AlF-NOTA-NOC for PET Imaging of Neuroendocrine Tumors: Comparison to [68Ga]Ga-DOTA/NOTA-NOC.

BACKGROUND: The somatostatin receptors 1-5 are overexpressed on neuroendocrine neoplasms and, as such, represent a favorable target for molecular imaging. This study investigates the potential of [18F]AlF-NOTA-[1-Nal3]-Octreotide and compares it in vivo to DOTA- and NOTA-[1-Nal3]-Octreotide radiolabeled with gallium-68. METHODS: DOTA- and NOTA-NOC were radiolabeled with gallium-68 and NOTA-NOC with [18F]AlF. Biodistributions of the three radioligands were evaluated in AR42J xenografted mice at 1 h p.i and for [18F]AlF at 3 h p.i. Preclinical PET/CT was applied to confirm the general uptake pattern. RESULTS: Gallium-68 was incorporated into DOTA- and NOTA-NOC in yields and radiochemical purities greater than 96.5%. NOTA-NOC was radiolabeled with [18F]AlF in yields of 38 ± 8% and radiochemical purity above 99% after purification. The biodistribution in tumor-bearing mice showed a high uptake in tumors of 26.4 ± 10.8 %ID/g for [68Ga]Ga-DOTA-NOC and 25.7 ± 5.8 %ID/g for [68Ga]Ga-NOTA-NOC. Additionally, [18F]AlF-NOTA-NOC exhibited a tumor uptake of 37.3 ± 10.5 %ID/g for [18F]AlF-NOTA-NOC, which further increased to 42.1 ± 5.3 %ID/g at 3 h p.i. CONCLUSIONS: The high tumor uptake of all radioligands was observed. However, [18F]AlF-NOTA-NOC surpassed the other clinically well-established radiotracers in vivo, especially at 3 h p.i. The tumor-to-blood and -liver ratios increased significantly over three hours for [18F]AlF-NOTA-NOC, making it possible to detect liver metastases. Therefore, [18F]AlF demonstrates promise as a surrogate pseudo-radiometal to gallium-68.

Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability.

Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies.