Toscano, M. | bioRxiv Science

bioRxiv2023

PD-L1 Restrains the PD-1hiNrp1loTGFb+ Treg to block IL6+ Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

PD-L1 functions as a suppressor of T cell activation and colonic inflammation. The consequence of and mechanism underlying these opposite functions of PD-L1 in colorectal cancer remains unknown. We report that global Cd274 deletion promotes inflammation-driven colorectal tumorigenesis. 16S rRNA and shotgun metagenomic sequencing revealed that loss of host PD-L1 leads to expansion of gut Ligilactobacillus murinus and activation of the AhR pathway in tumor-bearing mice. scRNA-seq analysis revealed that PD-L1 regulates PD-189Nrp11215 Treg, IL6+ neutrophils, and B cells in colorectal tumor. Treg expresses high level of TGF{beta} to recruit IL6+ neutrophils. IL6 inhibits activation of B and T cells. IL6 blockade or B cell activation via CD40 agonist increases CTL activation and suppresses colon tumor growth in vivo. Our findings determine that PD-L1 functions as a tumor suppressor in the context of inflammation-driven colorectal cancer and the PD-L1/L. murius/PD-189Nrp11215TGF{beta}+ Treg/IL6+ neutrophils pathway controls host cancer immunosurveillance and colorectal tumorigenesis. Key pointsGlobal deletion of Cd274 promotes inflammation-driven colorectal tumorigenesis. Loss of PD-L1 increases gut L. murinus and activates AhR pathway in colorectal tumor. PD-1hiTGF{beta}+Nrp1lo Treg recruits IL6+ neutrophils to inhibit B and T cell function in colorectal tumor. L. murinus and tryptophan metabolites connect PD-L1 and colorectal tumor immunosurveillance. Graphic summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/562132v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@2d23bcorg.highwire.dtl.DTLVardef@1852c8eorg.highwire.dtl.DTLVardef@304978org.highwire.dtl.DTLVardef@278c5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Defining variation in pre-human ecosystems can guide conservation: An example from a Caribbean coral reef

There is a consensus that Caribbean coral reefs are a pale shadow of what they once were, yet a reef’s pre-human state is typically assumed or estimated using space-for-time substitution approaches. These approaches may fail to account for past variation before human impact which could mislead conservation priorities and actions. In this study we use a suite of fossilised mid-Holocene (7.2-5.6 ka) fringing reefs in Caribbean Panama to define the Historical Range of Variation (HRV) in coral community structure before human-impact to provide context for the states of modern reefs in the same area. Using the abundances of coral taxa to quantify communities, we found that most of the modern coral communities exist in novel ecosystem states with no fossil precedence. We do however identify one modern reef that is indistinguishable in coral community structure from the mid-Holocene reefs. Reef-matrix cores show that the community on this reef has remained in a stable state for over 760 years, suggesting long-term resistance to the region-wide shift to novel states. Without historical context this robust and stable reef would be overlooked since it does not fulfil expectations of what a “pristine” coral reef should look like. This example illustrates how defining past variation using the fossil record can place modern degradation in historical context and improve conservation recommendations.View Full Text

paleontology↗