From 537d942b5e739425e2cc1280fe19824220773c77 Mon Sep 17 00:00:00 2001 From: ndwarshuis Date: Sun, 25 Jul 2021 22:59:33 -0400 Subject: [PATCH] FIX latex errors --- tex/thesis.tex | 63 ++++++++++++++++++++++++++------------------------ 1 file changed, 33 insertions(+), 30 deletions(-) diff --git a/tex/thesis.tex b/tex/thesis.tex index 19aecdb..38c94ce 100644 --- a/tex/thesis.tex +++ b/tex/thesis.tex @@ -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 phenotype44–46. 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 +phenotype44–46. 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 cells53–58. 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 phenotypes59–61. 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 cells53–58. 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 phenotypes59–61. 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}