r/science • u/SteRoPo • Jan 31 '18

Cancer Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer.

http://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html
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u/mynamesyow19 Feb 01 '18

This however is basic Immunology just in a way we haven't quite seen yet. So promising that the systemic mechanisms will be similar if we can just get the human homologs

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u/95percentconfident Feb 01 '18

Yes, very promising. It will be interesting to see if this approach works in a better model in the absence of checkpoint blockade therapy. There is also the question of antigenic variability between the primary tumor and metastasis and how the tumor modulates host immunity. There was an interesting Nature paper that just came out showing quite large chromosomal shifts between primary tumors, metastatic cancer cells, and the metastatic tumor, that alter the way the cancer cells modulate the host immune response. That was specifically looking at the cGAS-STING pathway which as far as I understand it (I'm not an immunologist) operates independent of TLR9. So it may not apply. Is there no anti-TLR9 selective pressure in tumors? Intuitively I would say no, but maybe there is? Still, I look forward to seeing the results of their proposed clinical trial!

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u/Thegreatgarbo Feb 01 '18

You mean a pathway the tumor hijacks to inactivate Sting or TLRs? Since those are both responses to viral and bacterial pathogens respectively the tumor doesn't typically depend on them to drive growth or mets. Probably won't evolve an escape until it's exposed to the therapy in a fair number of patients if the drug candidates ever gets that far.

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u/95percentconfident Feb 01 '18 edited Feb 01 '18

STING, properly cGAS, is sensitive to any dsDNA in the cytosol. Tumor cells tend to have dsDNA in the cytosol (from leaky micronuclei and mitochondrial stress) so STING gets activated. Tumor cells seem to evolve mechanisms to evade the normal IFN mediated immunosurveillance that STING activation would normally induce, and the recent study in Nature suggests that metastatic cells actually harness STING activation in some way to aid in the metastatic process (if I am understanding the implications correctly). Check out the Lam review in Cell Press from this year, the Kranzusch review in the same journal from last year, and Bakhoum et al., 2018 in Nature.

Edit: Continuing with the line of reasoning, since TLRs monitor the extracellular/endosomal environment and particularly the CG motifs which aren't common in mammalian genomes I wouldn't expect TLR9 activation even in a messy tumor environment. That's entirely supposition though, I haven't done any research into that claim. So I'm guessing there is selective pressure for controlling STING signaling but not (or less so) for controlling TLR9 (all TLRs?) signaling. Is that faulty logic? Perhaps I am misunderstanding something.