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.

Preparation and Evaluation of [F]AlF-NOTA-NOC for PET Imaging of Neuroendocrine Tumors: Comparison to [Ga]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 [F]AlF-NOTA-[1-Nal]-Octreotide and compares it in vivo to DOTA- and NOTA-[1-Nal]-Octreotide radiolabeled with gallium-68.

Methods: DOTA- and NOTA-NOC were radiolabeled with gallium-68 and NOTA-NOC with [F]AlF.

Targeting two distinct epitopes on human CD73 with a bispecific antibody improves anticancer activity.

Background: Immunosuppressive extracellular adenosine is generated by the enzymatic activity of CD73. In preclinical models, antibodies (Abs) targeting different epitopes on CD73 exert anticancer activity through distinct mechanisms such as inhibition of enzymatic activity, engagement of Fc receptors, and spatial redistribution of CD73.

Methods: Using controlled Fab arm exchange, we generated biparatopic bispecific antibodies (bsAbs) from parental anti-CD73 Abs with distinct anticancer activities.

The Cancer/Testis Antigen Gene Is Rarely Expressed in Malignancies but Can Be Epigenetically Activated Using DNA Methyltransferase and Histone Deacetylase Inhibitors.

Identification of novel tumor-specific targets is important for the future development of immunotherapeutic strategies using genetically engineered T cells or vaccines. In this study, we characterized the expression of VCX2, a member of the VCX/Y cancer/testis antigen family, in a large panel of normal tissues and tumors from multiple cancer types using immunohistochemical staining and RNA expression data. In normal tissues, VCX2 was detected in the germ cells of the testis at all stages of maturation but not in any somatic tissues.

Augmenting engineered T-cell strategies in solid cancers through epigenetic priming.

T-cell receptor (TCR)- and chimeric antigen receptor (CAR)-based adoptive cell transfer (ACT) has shown promising results in hematological malignancies, but remains immature in solid cancers. The challenges associated with identification of tumor-specific targets, the heterogenic antigen expression, limited T-cell trafficking to tumor sites and the hostile tumor microenvironment (TME), are all factors contributing to the limited efficacy of ACT therapies against solid tumors. Epigenetic priming of tumor cells and the microenvironment may be a way of overcoming these obstacles and improving the clinical efficacy of adoptive T-cell therapies in the future.

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.