FIX latex errors

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Nathan Dwarshuis 2021-07-25 22:59:33 -04:00
parent 3b28dc5612
commit 537d942b5e
1 changed files with 33 additions and 30 deletions

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@ -81,6 +81,9 @@
palindromic repeats}
\newacronym{mtt}{MTT}{3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide}
\newacronym{bmi}{BMI}{body mass index}
\newacronym{a2b1}{A2B1}{integrin $\upalpha$1$\upbeta$1}
\newacronym{a2b2}{A2B2}{integrin $\upalpha$1$\upbeta$2}
\newacronym{til}{TIL}{tumor infiltrating lymphocytes}
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
% SI units for uber nerds
@ -1403,27 +1406,27 @@ subsets to be included in CAR T cell therapy given a disease state.
% the signaling and why this might matter
There are several plausible explanations for the observed phenotypic differences
between beads and DMSs. First, the DMSs are composed of a collagen derivative
(gelatin); collagen has been shown to costimulate activated T cells via α1β1 and
α2β1 integrins, leading to enhanced proliferation, increased IFNγ production,
and upregulated CD25 (IL2Rα) surface expression8,10,11,41,42. Second, there is
evidence that providing a larger contact area for T cell activation provides
greater stimulation16,43; the DMSs have a rougher interface than the 5 µm
magnetic beads, and thus could facilitate these larger contact areas. Third, the
DMSs may allow the T cells to cluster more densely compared to beads, as
evidenced by the large clusters on the outside of the DMSs (Figure 1f) as well
as the significant fraction of DMSs found within their interiors (Supplemental
Figure 2a and b). This may alter the local cytokine environment and trigger
different signaling pathways. Particularly, IL15 and IL21 are secreted by T
cells and known to drive memory phenotype4446. We noted that the IL15 and IL21
concentration was higher in a majority of samples when comparing beads and DMSs
across multiple timepoints (Supplemental Figure 18) in addition to many other
cytokines. IL15 and IL21 are added exogenously to T cell cultures to enhance
memory frequency,45,47 and our data here suggest that the DMSs are better at
naturally producing these cytokines and limiting this need. Furthermore, IL15
unique signals in a trans manner in which IL15 is presented on IL15R to
neighboring cells48. The higher cell density in the DMS cultures would lead to
more of these trans interactions, and therefore upregulate the IL15 pathway and
lead to more memory T cells.
(gelatin); collagen has been shown to costimulate activated T cells via
\gls{a2b1} and \gls{a2b2}, leading to enhanced proliferation, increased
IFN$\upgamma$ production, and upregulated CD25 (IL2R$\upalpha$) surface
expression8,10,11,41,42. Second, there is evidence that providing a larger
contact area for T cell activation provides greater stimulation16,43; the DMSs
have a rougher interface than the 5 µm magnetic beads, and thus could facilitate
these larger contact areas. Third, the DMSs may allow the T cells to cluster
more densely compared to beads, as evidenced by the large clusters on the
outside of the DMSs (Figure 1f) as well as the significant fraction of DMSs
found within their interiors (Supplemental Figure 2a and b). This may alter the
local cytokine environment and trigger different signaling pathways.
Particularly, IL15 and IL21 are secreted by T cells and known to drive memory
phenotype4446. We noted that the IL15 and IL21 concentration was higher in a
majority of samples when comparing beads and DMSs across multiple timepoints
(Supplemental Figure 18) in addition to many other cytokines. IL15 and IL21 are
added exogenously to T cell cultures to enhance memory frequency,45,47 and our
data here suggest that the DMSs are better at naturally producing these
cytokines and limiting this need. Furthermore, IL15 unique signals in a trans
manner in which IL15 is presented on IL15R to neighboring cells48. The higher
cell density in the DMS cultures would lead to more of these trans interactions,
and therefore upregulate the IL15 pathway and lead to more memory T cells.
% TODO this mentions the DOE which is in the next aim
When analyzing all our experiments comprehensively using causal inference, we
@ -1531,15 +1534,15 @@ manufacturing companies.
Finally, while we have demonstrated the DMS system in the context of CAR T
cells, this method can theoretically be applied to any T cell immunotherapy
which responds to anti-CD3/CD28 mAb and cytokine stimulation. These include
tumor infiltrating lymphocytes (TILs), virus-specific T cells (VSTs), T cells
engineered to express γδTCR (TEGs), γδ T cells, T cells with transduced-TCR, and
CAR-TCR T cells5358. Similar to CD19-CARs used in liquid tumors, these T cell
immunotherapies would similarly benefit from the increased proliferative
capacity, metabolic fitness, migration, and engraftment potential characteristic
of naïve and memory phenotypes5961. Indeed, since these T cell immunotherapies
are activated and expanded with either soluble mAbs or bead-immobilized mAbs,
our system will likely serve as a drop-in substitution to provide these
benefits.
\glspl{til}, virus-specific T cells (VSTs), T cells engineered to express
$\upgamma\updelta$TCR (TEGs), $\upgamma\updelta$ T cells, T cells with
transduced-TCR, and CAR-TCR T cells5358. Similar to CD19-CARs used in liquid
tumors, these T cell immunotherapies would similarly benefit from the increased
proliferative capacity, metabolic fitness, migration, and engraftment potential
characteristic of naïve and memory phenotypes5961. Indeed, since these T cell
immunotherapies are activated and expanded with either soluble mAbs or
bead-immobilized mAbs, our system will likely serve as a drop-in substitution to
provide these benefits.
\chapter{aim 2}\label{aim2}