Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome

BackgroundBreast cancer (BC) progression to metastatic disease is the leading cause of death in women worldwide. Metastasis is driven by cancer stem cells (CSCs) and signals from their microenvironment. Interleukin (IL) 30 promotes BC progression, and its expression correlates with disease recurrence and mortality. Whether it acts by regulating BCSCs is unknown and could have significant therapeutic implications.MethodsHuman (h) and murine (m) BCSCs were tested for their production of and response to IL30 by using flow cytometry, confocal microscopy, proliferation and sphere-formation assays, and PCR array. Immunocompetent mice were used to investigate the role of BCSC-derived IL30 on tumor development and host outcome. TCGA PanCancer and Oncomine databases provided gene expression data from 1084 and 75 hBC samples, respectively, and immunostaining unveiled the BCSC microenvironment.ResultshBCSCs constitutively expressed IL30 as a membrane-anchored glycoprotein. Blocking IL30 hindered their proliferation and self-renewal efficiency, which were boosted by IL30 overexpression. IL30 regulation of immunity gene expression in human and murine BCSCs shared a significant induction of IL23 and CXCL10. Both immunoregulatory mediators stimulated BCSC proliferation and self-renewal, while their selective blockade dramatically hindered IL30-dependent BCSC proliferation and mammosphere formation. Orthotopic implantation of IL30-overexpressing mBCSCs, in syngeneic mice, gave rise to poorly differentiated and highly proliferating MYC+KLF4+LAG3+ tumors, which expressed CXCL10 and IL23, and were infiltrated by myeloid-derived cells, Foxp3+ T regulatory cells and NKp46+RORγt+ type 3 innate lymphoid cells, resulting in increased metastasis and reduced survival. In tumor tissues from patients with BC, expression of IL30 overlapped with that of CXCL10 and IL23, and ranked beyond the 95th percentile in a Triple-Negative enriched BC collection from the Oncomine Platform. CIBERSORTx highlighted a defective dendritic cell, CD4+ T and γδ T lymphocyte content and a prominent LAG3 expression in IL30highversus IL30low human BC samples from the TCGA PanCancer collection.ConclusionsConstitutive expression of membrane-bound IL30 regulates BCSC viability by juxtacrine signals and via second-level mediators, mainly CXCL10 and IL23. Their autocrine loops mediate much of the CSC growth factor activity of IL30, while their paracrine effect contributes to IL30 shaping of immune contexture. IL30-related immune subversion, which also emerged from computational analyses, strongly suggests that targeting IL30 can restrain the BCSC compartment and counteract BC progression.

Meningioma–Brain Crosstalk: A Scoping Review

Background: In recent years, it has become evident that the tumoral microenvironment (TME) plays a key role in the pathogenesis of various cancers. In meningiomas, however, the TME is poorly understood, and it is unknown if glia cells contribute to meningioma growth and behaviour. Objective: This scoping review investigates if the literature describes and substantiates tumour–brain crosstalk in meningiomas and summarises the current evidence regarding the role of the brain parenchyma in the pathogenesis of meningiomas. Methods: We identified studies through the electronic database PubMed. Articles describing glia cells and cytokines/chemokines in meningiomas were selected and reviewed. Results: Monocytes were detected as the most abundant infiltrating immune cells in meningiomas. Only brain-invasive meningiomas elicited a monocytic response at the tumour–brain interface. The expression of cytokines/chemokines in meningiomas has been studied to some extent, and some of them form autocrine loops in the tumour cells. Paracrine interactions between tumour cells and glia cells have not been explored. Conclusion: It is unknown to what extent meningiomas elicit an immune response in the brain parenchyma. We speculate that tumour–brain crosstalk might only be relevant in cases of invasive meningiomas that disrupt the pial–glial basement membrane.

Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma

Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor.