Connor Rosen Profile picture
Aug 14, 2018 16 tweets 4 min read Read on X
More on immune evasion in glioblastoma! Online now in @NatureMedicine, intracranial tumors drive sequestration of T cells in the bone marrow through downregulation of S1PR1 receptor surface expression. nature.com/articles/s4159…
GBM patients, including treatment-naive, and mice with a variety of intracranial tumors (regardless of tumor origin) show extremely low levels of circulating T cells and reduced spleen size, with accompanying increase in bone marrow T cells (especially naive T cells).
This seems to be due to lower S1PR1 on T cells, driven by ligand-independent internalization (RNA levels are identical between control and tumor-bearing mice and there is no increase of S1P in the tumor-bearing mice).
KO or antagonism of S1PR1 results in increased T cell sequestration in bone marrow during adoptive transfer, and a knock-in mouse that can't internalize S1PR1 do not experience bone marrow sequestration of T cells with intracranial tumors.
They then show that rescuing ability of T cells to avoid sequestration in the bone marrow (expressing non-internalizable S1PR1) improves outcome in combination with immunotherapy - 4-1BB agonism or 4-1BB agonist + anti-PD-1 combo (but not anti-PD-1 monotherapy, interestingly).
Importantly, they show that the S1P1-KI does not have any tumor benefit alone - sequestration is a redundant immune evasion strategy, and there are other suppression mechanisms in the tumor that block T cell activity even if the cells manage to get in.
Very interesting results on a novel immune evasion mechanism, and anything getting at the root of why GBM is so challenging and its unique immune evasion mechanisms is a very welcome finding! Also raises many new interesting questions...
How do intracranial tumors induce S1PR1 internalization, if it's not ligand-dependent? What about T cell entry into the brain itself - this paper shows bone marrow and periphery only, but is there a S1PR1-dependent defect in brain entry (consistent with FTY720 efficacy in MS)?
The kinetics of T cell entry to the bone marrow (Fig S3C) show it's 2 weeks before there's any increase in BM T cells, so it's probably an effect of persistent activity - but is it tumor intrinsic, or would any persistent brain inflammation drive this as a feedback response?
There's no S1P1-KO into Control (no tumor) adoptive transfer, so it's unclear if S1PR1 downregulation is sufficient to drive T cells into the bone marrow or if the tumors have other signals acting on the T cells that force them into the bone marrow instead of e.g. SLOs.
The supplement shows G-CSF rescues T cells from sequestration and synergizes with 4-1BB. What's the regulatory mechanism going on - is it acting indirectly on e.g. microglia to do something to the T cells? What cells are making / responding? Is G-CSF downregulated in GBM?
Recombinant G-CSF can be given to people, so that may be one way to tackle this axis, since enforcing S1PR1 surface expression is right now pharmacologically challenging. Would a Grk inhibitor to prevent internalization be safe?
Vaccination is big in GBM, and this paper might suggest one reason to favor it - naive T cells are more prone to sequestration, so there's no T cells around to prime. Overcoming that with a vaccine may drive memory formation, and those cells then can get into the tumor site.
And since I like NK cells in GBM (), it's interesting to note that NK cells don't show any sequestration in the tumor-bearing mice, which is consistent with a lower level of S1PR1 expression.
Overall this paper shows some very exciting and interesting results from GBM patients and mouse models, and opens up a lot of areas for understanding a new immune evasion mechanism and some very interesting brain immunology. #Glioblastoma #Immunotherapy #Neuroimmunology
Also, @NatureMedicine, there are some confusing figure references, the text points to Fig 6F for PD-1 results but that's actually shown in Fig S6B, and the G-CSF results are shown in Fig S6c-e but referenced in the text as S6a-c.

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More from @connor_rosen

Sep 25, 2020
Here’s a thread on anti-interferon autoantibodies, viral infections, and human immunology. This is less a covid thread, and more an anti-covid thread, if anything…
Summary: anti-IFN auto-Abs may be reflective of chronic inflammation, and may pre-exist in vulnerable groups at high levels. Presence in severe covid cases may therefore reflect basal immune variation which impacts covid, rather than a special covid-specific phenomenon.
This is prompted based on the new Science paper on autoantibodies against Type I IFNs in severe covid patients (science.sciencemag.org/content/early/…). Basically, ~10% of severe covid patients had high titer anti-IFNa antibodies that were functionally neutralizing.
Read 23 tweets
Jun 2, 2020
The message is very simple. #BlackLivesMatter
I'm grateful that others have put together resources like bit.ly/ANTIRACISMRESO…, which has helped me learn to be better. So You Want To Talk About Race by @IjeomaOluo and How To Be An Antiracist by @DrIbram have been amazing, and I'm looking forward to reading deeper.
I haven't seen a similar central resource for donations, but various recommendations led me to eji.org (Equal Justice initiative, focused on criminal justice reform and education), voterparticipation.org (get people registered to vote)...
Read 5 tweets
Apr 21, 2020
The story about mitochondria being ~10° hotter than the rest of the cell, published @PLOSBiology a couple years ago (journals.plos.org/plosbiology/ar…) got some cool, albeit indirect, support recently @naturemethods#Biophysics #CellBiology
The original paper, which was mainly based on the temperature-dependent fluorescence of a mitochondria-targeting probe, was accompanied by a “Primer” (journals.plos.org/plosbiology/ar…) highlighting potential flaws and implications, a special sort-of-peer-review step by PLOS Biology.
This new awesome resource @naturemethods - nature.com/articles/s4159… - offers some intriguing orthogonal validation. This is a proteome-wide study of protein thermal stability across 13 organisms, conducted using a mass-spec-based approach.
Read 11 tweets
Nov 22, 2019
Super neat story on how cellular quality control impacts the mutational landscape of proteins - beneficial mutations in DHFR during deep mutational scanning are totally altered dependent on cellular QC #Biophysics #Evolution biorxiv.org/content/10.110… Way to go! @KortemmeLab
In an initial DMS experiment on DHFR, there were a large number (25% of all sequences!) of advantageous mutations spread across the whole protein. Reintroduction of QC protein Lon reduced the number of advantageous mutants and lowered average benefit of those mutations
Changes in selection coefficient (the “advantageous-ness”) were most striking at hydrophobic/aromatic residues and buried residues - and these correlate with Tm changes of variants. So Lon seems to be imposing higher standards on DHFR, particularly for destabilizing core mutants
Read 5 tweets
Nov 20, 2019
A couple interesting bits of preliminary data on Langerhans cells and the huLangerin mouse used to study them. Effects of developmental absence of LCs on keratinocytes and T cells, and huLangerin-YFP labels some neurons (check your Cre mice!) #Genetics #Immunology
First - effect of loss of LCs in the huLangerin-DTA mice - biorxiv.org/content/10.110…. Bulk RNA-seq showed changes in keratinocytes and dendritic epidermal T cells, including cell-type specific changes (e.g. loss of IL17 pathway in DETCs).
Unfortunately, underlying data (either gene expression tables or raw RNA-seq data) don’t currently seem available, but hopefully the authors get that up shortly. Will be interesting to look at and prompt some hypotheses about how LCs control homeostasis and development.
Read 5 tweets
Nov 18, 2019
CYTOF analysis of human neutrophils - 7 populations with differing phagocytosis, ROS, and FACS-compatible surface marker phenotypes. Changes in distribution between healthy + melanoma patients. #Immunology #Cancer #Neutrophils biorxiv.org/content/10.110…
Circulating neutrophil precursors, aged neutrophils, and a few populations of mature and immature neutrophils. Melanoma stage correlates with loss of dominant N2 (mature, ROS++, lowly phagocytic), and increase of N5 (immature, non-proliferative, ROS+, lowly phagocytic).
Interesting to note the phagocytosis-SSC staining in Fig4A - big changes in SSC for some populations with zymosan, others not so much - degranulation, different phagosomes…? Similarly, bimodal peaks for ROS production in same populations… Image
Read 4 tweets

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