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