cyclic-guanosine-monophosphate-adenosine-monophosphate and Neoplasm-Metastasis

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.

Topics: Animals; Humans; Hydrolysis; Immunotherapy; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasms; Nucleotides, Cyclic; Tumor Escape

The second messenger 2'3'-cyclic-GMP-AMP (cGAMP) is thought to be transmitted from brain carcinomas to astrocytes via gap junctions, which functions to promote metastasis in the brain parenchyma. In the current study, we established a method to introduce cGAMP into astrocytes, which simulates the state of astrocytes that have been invaded by cGAMP around tumors. Astrocytes incorporating cGAMP were analyzed by metabolomics, which demonstrated that cGAMP increased glutamate production and astrocyte secretion. The same trend was observed for γ-aminobutyric acid (GABA). Conversely, glutamine production and secretion were decreased by cGAMP treatment. Due to the fundamental role of astrocytes in regulation of the glutamine-glutamate cycle, such metabolic changes may represent a potential mechanism and therapeutic target for alteration of the central nervous system (CNS) environment and the malignant transformation of brain carcinomas.

Topics: Animals; Astrocytes; Brain Neoplasms; gamma-Aminobutyric Acid; Glucose; Neoplasm Metastasis; Nucleotides, Cyclic; Primary Cell Culture; Rats, Wistar

The leading cause of mortality due to colorectal cancer (CRC) is highly associated with the development of liver metastases. Recently, we described cGAMP that is closely related to the metastatic state wherein the progress of metastatic tumors is associated with favorable outcomes in a zebrafish xenograft model. cGAMP was administered and the expression levels of type-I interferons were induced amongst tumor tissues to illuminate the overall measure of the induced STING/STAT3 axis in colorectal liver metastases. Furthermore, cGAMP-STING dependent STAT3 activation resulted in the inhibition of tumor cell proliferation, viability, and invasion in vitro. The subtotal reduction in tumor growth attributed to a large number of infiltrating inflammatory cells in vivo. We showed that cGAMP inhibited migration through angiogenesis by up-regulating IL-2, TNF-α, and IFN-γ, whereas STAT3 down-regulation inhibited CXCL8, BCL-2, and VEGFA expression. The importance of cGAMP in inhibiting the invasion front of CRC confirmed that the cGAMP dependent activation of STING/STAT3 axis played a key role in the inhibition of tumor progression.

Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Disease Models, Animal; Heterografts; Liver Neoplasms; Membrane Proteins; Neoplasm Metastasis; Nucleotides, Cyclic; Signal Transduction; STAT3 Transcription Factor; Zebrafish; Zebrafish Proteins

Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutics that activate innate immunity to increase tumour immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance and inefficient transport to the cytosol where STING is localized. Here, we describe STING-activating nanoparticles (STING-NPs)-rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). STING-NPs increase the biological potency of cGAMP, enhance STING signalling in the tumour microenvironment and sentinel lymph node, and convert immunosuppressive tumours to immunogenic, tumoricidal microenvironments. This leads to enhanced therapeutic efficacy of cGAMP, inhibition of tumour growth, increased rates of long-term survival, improved response to immune checkpoint blockade and induction of immunological memory that protects against tumour rechallenge. We validate STING-NPs in freshly isolated human melanoma tissue, highlighting their potential to improve clinical outcomes of immunotherapy.

Topics: Animals; Cytosol; Endosomes; Female; Humans; Immunotherapy; Inflammation; Membrane Proteins; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasm Metastasis; Neoplasms; Nucleotides, Cyclic; Polymers; T-Lymphocytes; Tumor Microenvironment