Thread by @connor_rosen

Reading this review on immunotherapy in glioblastoma (nature.com/articles/s4157…) @NatRevClinOncol . A few odds and ends make me wonder - is there going to be a special role for NK cells in glioblastoma? Should we be aiming to target them for more effective therapies?

Checkpoint blockade hasn’t shown much efficacy in glioblastoma, in line with relatively low mutational burden (nejm.org/doi/full/10.10…) @NEJM. Also in line with the brain as “immunoprivileged”, or at least as a place with "unusual" immune activity.

First started thinking about NK cells in GBM after reading excellent study on PDGF-DD as an activating NK cell ligand (sciencedirect.com/science/articl…) @CellCellPress - striking human data from GBM cohorts, especially with greater infiltration of NK cells than T cells into tumor.

Then there’s the oncolytic virus angle - everything from preclinical with Zika (jem.rupress.org/content/early/…) @JExpMed through to very new clinical results with nonpathogenic poliovirus (nejm.org/doi/full/10.10…) @NEJM

Oncolytic virotherapy can, in addition to direct killing of tumor cells, also increase immune responses - and if glioblastoma is really a poorly T-cell infiltrated tumor, then NK cells provide a good anti-viral response to further kill infected cells.

And NK cells can definitely get in and kill oncolytic-virus-infected glioblastoma cells - nature.com/articles/nm.30… @NatureMedicine. In that case, they were actually too efficient and limited therapy efficacy by killing so quickly that the virus couldn’t spread.

(Aside: it’s interesting that CD155, the poliovirus receptor, is a ligand for DNAM1/TIGIT. And while *neurovirulence* of poliovirus seems to be driven by IRES, *neurotropism* isn’t… Does internalization of CD155 by poliovirus internalization matter for NK cell function?)

I’m seeing conflicting data on NK cell infiltration in glioblastomas, especially relative to T cells - e.g. link.springer.com/article/10.100…, jhoonline.biomedcentral.com/articles/10.11…, and clincancerres.aacrjournals.org/content/early/…. So it’s hard to know where that angle comes in.

But things get weirder, suggesting more roles for NK cells than I naively expected - a DC vaccine in glioblastoma is inducing an NK cell response that’s more important for survival than CD8+ T cells? tandfonline.com/doi/full/10.10…

And, in line with interesting things happening in the brain immunologically, NK cells could be doing wildly different things - and there’s plenty of evidence around that they may actually be taking on anti-inflammatory roles in the brain.

See e.g. pnas.org/content/113/21… @PNASNews, sciencedirect.com/science/articl… @ImmunityCP, recent report using IL-15 to activate suppressive NK cells in Cerebral Malaria, and nature.com/articles/nri30… @NatRevImmunol (NK cells are killing microglia in MS/EAE?)

So, while there’s a lot of uncertainty and some conflicting evidence (in my light reading alone!), I think the weight is leaning towards the idea that we should be taking a closer look at NK cells in glioblastoma, especially as targets for new immunotherapies.

Are they killing APCs and T cells (as in MS/EAE)? Are they helpful or hurting in oncolytic virotherapy (in humans specifically)? The impairment of oHSV virotherapy was mediated by NK-receptor ligands upregulated by the virus - maybe that's not the case in zika / poliovirus?

I didn't find a definitive answer on the rate on MHC Class I loss in GBM, which would be good to know. And a little more definitive answer on infiltration, and the exact phenotype of whatever NK cells are in the tumor, would be good to see as well.

There’s some other biology that, as an armchair fan of NK cells (at best) and even less knowledgable about neuroimmunology, I’m sure I’m missing. Didn’t even get to skim plenty of other interesting NK-in-the-brain stories, like this one ncbi.nlm.nih.gov/pubmed/28314594.

But at a high level, it looks like there are lots of opportunities for new science, a deeper understanding of NK cells in the brain, and perhaps better outcomes for a still-horrifying disease. #Glioblastoma #Immunotherapy #NaturalKillerCells