Biology subjects

Poschel, D. B.

Publications and source records attributed to Poschel, D. B..

4 recordsLinked to original sources

bioRxiv2026

Multi-compartment immune and tumor cell reprogramming by IFNa2 overcomes colon cancer immunotherapy resistance

Approximately 85-90% of colorectal cancers (CRC) are microsatellite stable and resist immune checkpoint inhibitors (ICI). The recent success of intismeran, a lipid nanoparticle (LNP)-delivered mRNA encoding patient-specific tumor antigens, enhances pembrolizumab responses, showing that LNP-delivered nucleic acids can render ICI-resistant tumors responsive by supplying what the tumor microenvironment lacks. Because an IFN-responsive phenotype predicts CRC response to checkpoint blockade and tumor cell PD-L1 represses IFN-I, we asked whether delivering the missing cytokine, rather than antigen, achieves the same conversion. Here we show that PD-1 blockade failed even when initiated before tumor seeding, yet deleting tumor cell PD-L1 abolished colon cancer lung metastasis, implicating a tumor-intrinsic PD-L1 function that antibody blockade does not neutralize. An LNP-encapsulated IFN2-encoding nanoplasmid (LNP-IFN2) transfected tumor cells within lung metastases, converting them into a self-sustaining and tumor-restricted IFN2 source. LNP-IFN2 suppressed colon cancer lung metastasis in syngeneic and humanized mouse models and sensitized these ICI-resistant tumors to PD-1 blockade. Efficacy improved further with neutralization of co-induced IL6. scRNA-Seq revealed multi-compartment reprogramming: SPP1+ macrophages acquired apoptotic signatures as IFN-responsive monocytes replaced them, progenitor-exhausted T cells exited quiescence and expanded, and tumor cells exited a high-cycling state, gained antigen presentation, and shifted away from cuproptosis resistance. The treated microenvironment transcriptionally recapitulated pembrolizumab-responder signatures, positioning LNP-IFN2 as an off-the-shelf nanomedicine for ICI-resistant CRC.

immunology↗

bioRxiv2026

B cell-intrinsic IRF8 transcriptionally reprograms antigen presentation to sustain CD8⁺ T cell antitumor immunity

Interferon regulatory factor 8 (IRF8) is a master transcription factor of myeloid differentiation, but whether IRF8 intrinsically controls B cell function in tumors remains unknown. Using paired single-cell transcriptomic and chromatin accessibility profiling of tumors from wild-type and Irf8-deficient mice, we identify a B cell-intrinsic IRF8 axis regulating antigen presentation and sustaining anti-tumor CD8 T cell immunity. IRF8 establishes conserved chromatin accessibility programs across myeloid cells and plasmablasts centered on antigen processing and MHC class I presentation, but engages distinct motifs by lineage: myeloid cells preferentially utilize ISRE and ETS-composite elements, whereas plasmablasts are selectively enriched for EICE elements, reflecting B lineage-specific IRF8-IRF4 cooperation. Loss of IRF8 disrupts these programs, skews B cells toward plasmablast differentiation and reduces antigen presentation machinery. B cell depletion accelerated tumor growth, while CD40 agonism activated B cells, expanded T cells, and enhanced anti-tumor immunity. B cell-specific IRF8 deletion alone accelerated tumor growth, establishing a cell-intrinsic requirement independent of myeloid IRF8 function. The IRF8-regulated B cell signature was enriched in PD-1 blockade cancer patient responders, and plasmablast abundance correlated with response in pembrolizumab-treated cancer patients. These findings establish IRF8 as a lineage-adapted regulator of antigen presentation and define the IRF8-B cell axis as a determinant of anti-tumor immunity. HighlightsIRF8 establishes a conserved chromatin accessibility across tumor-infiltrating myeloid and B cells Myeloid cells engage ISRE motifs, whereas plasmablasts rely on EICE motifs as IRF8 lineage-specific cis-regulation IRF8 regulates an antigen presentation in B cells to sustain anti-tumor T cell immunity B cell-intrinsic IRF8 transcription signature predicts patient response to PD-1 blockade immunotherapy

immunology↗

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↗

bioRxiv2021

Tumor PD-L1 selectively suppresses type I interferon in myeloid cells to suppress CTL recruitment to promote lung metastasis

The mechanism underlying tumor cell PD-L1 (tPD-L1) induction of immune suppression through T cell PD-1 is well-known, but the mechanism underlying tPD-L1 induction of immune suppression via an intermediate cell is incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activation and lytic function when only tumor cells and CTLs are present. Strikingly, knocking out PD-L1 in tumor cells has no effect on primary tumor growth, but significantly decreases lung metastasis in a CTL-dependent manner. Depletion of myeloid cells impaired tPD-L1 promotion of lung metastasis. Single-cell RNA sequencing revealed that tPD-L1 engages myeloid PD-1 (mPD-1) to antagonize type I interferon (IFN-I) and STAT1 signaling to repress Cxcl9 and Cxcl10 expression to impair CTL recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. Our data determines that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9/10 axis controls CTL tumor infiltration in lung metastasis.

cancer biology↗