IL-23p19 has an inside job in endothelial cells

IL-12 cytokine family is full of surprises. Ordinarily, these cytokines (IL-12, IL-23, IL-27, IL-35) are made of two heterodimeric sub-units. But one after another, each of the sub-units were found to have an independent function.  

Latest in these series is a study from Science Signaling that showed that human endothelial cells express intra-cellular IL-23p19 that signals via gp130 molecules mimicking IL-6.

Initially, the authors showed that endothelial cells from Giant-cell arteritis (GCA) patients express IL-23p19 subunit, but not another IL-23p40 subunit (while I support fully-human studies, in controversial situations such as this, I preferred if the authors have included confirmation staining on IL-23p19 KO cell from KO mice or CRISPR/Cas9 edited IL-23p19 KO human cells). 

Next, in vitro experiments with primary human umbilical vein endothelial cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs) confirmed selective expression of IL-23p19 within endothelial cells in response to pro-inflammatory signaling.

IL-23p19 was detected in endothelial cell lysate but not in supernatants, suggesting that it was intra-cellular protein and wasn't secreted in culture medium.

Mechanistically, IL-23p19 transduced endothelial cells up-regulated adhesion molecules (VCAM-1, ICAM-1, PECAM-1) and induced gp130-dependent STAT3 activation.

The authors hypothesized that IL-23p19 could be similar to viral IL-6 (vIL-6), a viral cytokine product of human herpesvirus 8 (HHV-8, also known as Kaposi’s sarcoma-associated herpesvirus).

In summary, this study provided evidence that in humans IL-23p19 could have an independent biological function in endothelial cells by promoting adhesion and recruitment of inflammatory cells thus contributed to vasculitis.

David Usharauli

Tumor endothelial cells, not DCs, initiate anti-tumor IFN-β response to STING agonist

PNAS has published very interesting study in tumor immunity. Some of you might know endogenous DNA recognition complex made of cGAS-STING-IRF3 axis plays an important role in spontaneous anti-tumor activity observed in clinics in some cancer patients.

Immunologists already knew few years back that type I IFN system, rather than TLR system, facilitated natural, spontaneous priming of endogenous anti-tumor T cells. However, they did not know how it worked. Only after discovery of STING-cGAS the scientists made a connection between endogenous [tumor] DNA recognition and type I IFN in anti-tumor activity. Naturally it was assumed that antigen-presenting cells, such as DCs or macrophages, were the major players in STING anti-tumor "initiation" pathway.

Now, Swiss scientists provided evidence that when tumor-bearing mice were injected with STING agonist, cyclic dinucleotide GMP-AMP (cGAMP), it was endothelial cells rather than DCs that were responding to cGAMP by secreting IFN-β.

Initially, the authors showed that in murine B16 melanoma model STING was important for anti-cancer effect of intra-tumorally delivered cGAMP. 1/3 of cGAMP treated mice survived long-term. In addition, cGAMP injection showed synergy with anti-CTLA4/PD1 immunotherapy.

Next, the authors showed that anti-tumor CD8 T cell priming with cGAMP required functional type I IFN system.

In addition, these experiments revealed that anti-tumor effect of injected cGAMP was entirely depended on type I IFN responsiveness.

Surprisingly, analysis of tumor tissue showed that it was tumor vasculature endothelial cells, not DCs, that were IFN-β positive after cGAMP injection.

In vitro experiments confirmed that endothelial cells were specifically responding to cGAMP and tumor DNA.

In summary these results points to a complex interplay between tumor vasculature, tumor DNA and local anti-tumor T cell priming. It must be emphasized here that the authors had conducted short-term tumor challenge experiments here in most part and did not show whether cGAMP injection primed functional anti-tumor memory response in long term, for example by secondary tumor challenge.

David Usharauli