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XIAP-coordinated PKC signaling overcomes immunotherapy resistance via immunogenic rewiring to empower therapeutic rechallenge [RNA-Seq]

ABSTRACT: Immune-checkpoint blockade (ICB) against PD-1/PD-L1 has transformed cancer care, yet primary and acquired resistance limit its reach. By profiling substrate-based protein kinase C (PKC) activity, rather than pan-PKC expression, we uncover a superior biomarker predicting survival and anti-PD-1 responsiveness in non-small cell lung cancer (NSCLC). Critically, pharmacological pan-PKC inhibition overcomes anti-PD-1 resistance across diverse preclinical models through a coordinated immunologic program. Specifically, PKC blockade triggers Caspase-3/GSDME-dependent immunogenic cell death (ICD) with ATP/HMGB1 release. It concurrently reprograms the tumor microenvironment (TME) by enriching CD8+ T cells and regulatory T cells (Tregs) in a CCR5-dependent manner, while inducing tumor-intrinsic PD-L1 degradation to sustain CD8+ T cell function. Mechanistically, targeting PKC destabilizes XIAP, whose degradation not only unleashes caspase-mediated ICD and PD-L1 degradation but also licenses CCL4 secretion for CCR5-centric TME rewiring. Importantly, PKC blockade synergizes exclusively with anti-CTLA4 by selectively depleting intratumoral Tregs, providing a rational rechallenge regimen for anti-PD-1-refractory malignancies. Our findings establish PKC activity as a crucial biomarker and validate PKC inhibition as a translatable strategy to dismantle ICB resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE303940 | GEO | 2026/05/16

REPOSITORIES: GEO

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XIAP-coordinated PKC signaling overcomes immunotherapy resistance via immunogenic rewiring to empower therapeutic rechallenge [scRNA-seq]

Project description:Immune-checkpoint blockade (ICB) against PD-1/PD-L1 has transformed cancer care, yet primary and acquired resistance limit its reach. By profiling substrate-based protein kinase C (PKC) activity, rather than pan-PKC expression, we uncover a superior biomarker predicting survival and anti-PD-1 responsiveness in non-small cell lung cancer (NSCLC). Critically, pharmacological pan-PKC inhibition overcomes anti-PD-1 resistance across diverse preclinical models through a coordinated immunologic program. Specifically, PKC blockade triggers Caspase-3/GSDME-dependent immunogenic cell death (ICD) with ATP/HMGB1 release. It concurrently reprograms the tumor microenvironment (TME) by enriching CD8+ T cells and regulatory T cells (Tregs) in a CCR5-dependent manner, while inducing tumor-intrinsic PD-L1 degradation to sustain CD8+ T cell function. Mechanistically, targeting PKC destabilizes XIAP, whose degradation not only unleashes caspase-mediated ICD and PD-L1 degradation but also licenses CCL4 secretion for CCR5-centric TME rewiring. Importantly, PKC blockade synergizes exclusively with anti-CTLA4 by selectively depleting intratumoral Tregs, providing a rational rechallenge regimen for anti-PD-1-refractory malignancies. Our findings establish PKC activity as a crucial biomarker and validate PKC inhibition as a translatable strategy to dismantle ICB resistance.

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2026-01-16 | PXD064698 | Pride

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ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis [RNA-seq, anti-PD-L1 therapy]

Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.

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ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis

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Project description:Testing for PD-L1 expression by immunohistochemistry (IHC) is used to predict immune checkpoint blockade (ICB) benefit but has performed inconsistently in urothelial cancer (UC) clinical trials. Different approaches are used for PD-L1 IHC. We analyzed paired PD-L1 IHC data on UC samples using the SP142 and 22C3 assays from the phase 3 IMvigor130 trial and found discordant findings summarized by four phenotypes: PD-L1 positive by both assays (PD-L1 double positive; PD-L1DP), PD-L1 positive by the SP142 assay only (SP142 single positive; SP142SP), PD-L1 positive by the 22C3 assay only (22C3 single positive; 22C3SP), and PD-L1 negative by both assays double negative (PD-L1 double negative; PD-L1DN). PD-L1DP and SP142SP UCs were associated with more favorable ICB outcomes and increased dendritic-cell (DC) infiltration. SP142 PD-L1 staining co-localized with DC-LAMP, a DC marker, while 22C3 staining was more diffuse. 22C3SP UCs, associated with worse outcomes, were enriched in tumor cell–dominant PD-L1 expression. Multiplex IHC in an independent ICB-treated cohort confirmed that tumor cell–dominant PD-L1 expression was associated with shorter survival. Using different PD-L1 assays, we uncovered that SP142 may preferentially stain PD-L1–expressing DCs, key to orchestrating antitumor immunity, while tumor cell–dominant PD-L1 expression, which underlyies a subset of “PD-L1 positive” specimens, is associated with poor ICB outcomes.

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