Biology subjects

Strandberg, J.

Publications and source records attributed to Strandberg, J..

3 recordsLinked to original sources

bioRxiv2024

ITGB6 inhibition stimulates anti-tumor responses in immunocompetent mouse models of head & neck squamous cell carcinoma and pancreatic adenocarcinoma

ITGB6, the gene encoding the {beta}6 subunit of integrin v{beta}6, is a potent prognostic marker across multiple cancer types. As a major activator of latent TGF{beta}, v{beta}6, and consequently, ITGB6, has considerable therapeutic implications due to the immunosuppressive effect that activated TGF{beta} has on the tumor microenvironment. The present study identifies ITGB6 as a potent target for inducing an immune-mediated anti-tumor response. ITGB6 is highly upregulated in various squamous cell carcinomas and pancreatic adenocarcinomas, allowing it to disrupt tumor-immune cell signaling, while avoiding the widespread side-effects of systemic TGF{beta} inhibition. Genetic knockout of ITGB6 in heterotopically injected head and neck squamous cell carcinoma and pancreatic adenocarcinoma cell lines showed markedly reduced tumor progression in immunocompetent mice. Additionally, co-cultures of human squamous cell carcinoma cell lines and human T-cells showed increased T-cell killing upon cancer cell ITGB6 inhibition. Colony formation experiments give further evidence that the reduction in tumor growth observed upon ITGB6 inhibition in vivo is through immunological clearance of cancer cells and not merely through intrinsic factors. Analysis of The Cancer Genome Atlas (TCGA) revealed not only the high prognostic value of ITGB6 on overall survival but also that high ITGB6 expression in patients is often associated with an inferior response to -PD-1 and -PD-L1 immune checkpoint blockade. The potent anti-tumor immune response observed both in vitro and in vivo upon ITGB6 inhibition, combined with our analysis of RNA-seq data from immune checkpoint blockade-treated patients, encourages the development of ITGB6 blockade and immunotherapy combination regimes. Further pre-clinical studies will serve to facilitate the translation of our findings into therapeutic clinical trials of combination therapies for treating immunotherapy-resistant cancers. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/590156v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@162546aorg.highwire.dtl.DTLVardef@9422d6org.highwire.dtl.DTLVardef@17b4a5eorg.highwire.dtl.DTLVardef@14f903d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Hebbian activity only temporarily stabilizes synaptic transmission at CA3 - CA1 synapses in the developing hippocampus

Prolonged low frequency (0.05-1 Hz) stimulation of previously non-stimulated (naive) CA3-CA1 synapses in the developing hippocampus results in a profound synaptic depression explained by a postsynaptic AMPA silencing. It has been proposed that Hebbian activity can stabilize the synapses by preventing such depression. Using field recordings, we have examined to which extent strong repeated high frequency tetanization simulating Hebbian activity results in such prevention. The tetanization resulted within minutes in a field EPSP potentiation to 150-170% of the naive field EPSP level which remained unaltered if stimulation was suspended. If test pulse stimulation (0.2 Hz) was allowed to continue after the tetanization the field EPSP continuously decreased and was after 2700 stimuli depressed by 75% from the potentiated level. This depression did not differ in relative terms from that induced in naive synapses (by 82% from the naive level). The long-lasting component of this depression revealed by a subsequent 30 min stimulus interruption (by 59% from the potentiated level) did not differ from that of naive synapses (by 66% from the naive level). This equal relative degree of depression of tetanized and naive synapses was also observed following 2700 stimuli at 1 Hz. On the other hand, when examined at earlier time points during the test pulse stimulation (e.g. after 400-900 stimuli) tetanized synapses were less depressed than naive synapses, and the long-lasting depression after 900 stimuli at 1 Hz was only half that observed in naive synapses. This effect of tetanization was observed independently of whether the 1 Hz stimulation was commenced 15 min or 2 hours after the tetanization. In conclusion, while a strong preceding tetanization results in a partial stabilization of transmission at CA3-CA1 synapses in the developing hippocampus, this effect appears only temporary. This temporary effect is not linked to time after tetanization but to the number of low frequency stimuli given.

neuroscience↗

bioRxiv2023

TRAIL agonists rescue mice from radiation-induced lung injury

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. One Sentence SummaryPrevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-{psi}-irradiation by short- term treatment with innate immune TRAIL pathway agonists

pathology↗