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Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8 + T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC. Irreversible electroporation (IRE) has been approved as ablation therapy for pancreatic ductal adenocarcinoma (PDAC). Here, the authors show that, in mouse models, IRE reverses the immunosuppressive microenvironment of PDAC resulting in increased and durable response when combined with PD1 checkpoint inhibition therapy.

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers “cold” tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A “response score” was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions. The molecular mechanisms of resistance to immune checkpoint therapy remain elusive. Here, the authors perform immunogenomic analysis of TCGA data and data from clinical trials for antiPD-1/PD-L1 therapy and highlight the association of 9p21 loss with a cold tumor microenvironment and resistance to therapy.

Overcoming immune resistance mechanisms in patients with cancer is critical for successful immunotherapy. A new study now identifies LIMIT as an immunogenic long non-coding RNA (lncRNA) that intrinsically regulates anti-tumour immune responses, thereby highlighting the therapeutic potential of targeting lncRNAs to improve the outcome of cancer immunotherapy.

Aerosols significantly impact the brightness temperature (BT) in thermal infrared (IR) channels, and ignoring their effects can lead to relatively large observation-minus-background (OMB) bias in radiance calculations. The accuracy of aerosol datasets is essential for BT simulations and bias reduction. This study incorporated aerosol reanalysis datasets from the Modern-Era Retrospective Analysis for Research and Applications, Version 2 (MERRA-2) and Copernicus Atmosphere Monitoring Service (CAMS) into the Advanced Radiative Transfer Modeling System (ARMS) to compare their impacts on BT simulations from the Geostationary Interferometric Infrared Sounder (GIIRS) and their effectiveness in reducing OMB biases. The results showed that, for a sandstorm event on 10 April 2023, incorporating total aerosol data from the MERRA-2 improved the BT simulations by 0.56 K on average, surpassing CAMS’s 0.11 K improvement. Dust aerosols notably impacted the BT, with the MERRA-2 showing a 0.17 K improvement versus CAMS’s 0.06 K due to variations in the peak aerosol level, thickness, and column mass density. Improvements for sea salt and carbonaceous aerosols were concentrated in the South China Sea and Bay of Bengal, where the MERRA-2 outperformed CAMS. For sulfate aerosols, the MERRA-2 excelled in the Bohai Sea and southern Bay of Bengal, while CAMS was better in the northern Bay of Bengal. These findings provide guidance for aerosol assimilation and retrieval, emphasizing the importance of quality control and bias correction in data assimilation systems.

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy. It has been shown that targeting receptor-interacting protein kinase 1 (RIPK1) can improve response to immune checkpoint inhibitors. Here, using PROTAC technology, the authors report the design and characterization of a RIPK1 degrader, enhancing anti-tumor immunity in preclinical cancer models.

T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo. Mechanistic studies reveal that HSP90 inhibition results in upregulation of interferon response genes, which are essential for the enhanced killing of ganetespib treated melanoma cells by T cells. Taken together, these findings provide evidence that HSP90 inhibition can potentiate T-cell-mediated anti-tumor immune responses, and rationale to explore the combination of immunotherapy and HSP90 inhibitors. Many patients fail to respond to T cell based immunotherapies. Here, the authors, through a high-throughput screening, identify HSP90 inhibitors as a class of preferred drugs for treatment combination with immunotherapy.

CXCR5 mediates homing of both B and follicular helper T (TFH) cells into follicles of secondary lymphoid organs. We found that CXCR5+CD8+ T cells are present in human tonsils and follicular lymphoma, inhibit TFH-mediated B cell differentiation, and exhibit strong cytotoxic activity. Consistent with these findings, adoptive transfer of CXCR5+CD8+ T cells into an animal model of lymphoma resulted in significantly greater antitumor activity than CXCR5−CD8+ T cells. Furthermore, RNA-Seq-based transcriptional profiling revealed 77 differentially expressed genes unique to CXCR5+CD8+ T cells. Among these, a signature comprised of 33 upregulated genes correlated with improved survival in follicular lymphoma patients. We also showed that CXCR5+CD8+ T cells could be induced and expanded ex vivo using IL-23 plus TGF-β, suggesting a possible strategy to generate these cells for clinical application. In summary, our study identified CXCR5+CD8+ T cells as a distinct T cell subset with ability to suppress TFH-mediated B cell differentiation, exert strong antitumor activity, and confer favorable prognosis in follicular lymphoma patients.

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated, and harbors genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide further resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies. Amnesic screening methods are useful to discover host factors that are important for SARS-CoV2 infection. Here the authors use a CRISPR screen to identify three anti-viral factors, which are associated with the coagulation system, and two pro-viral candidates and then use individual genetic deletion experiments to characterise their effect.

CD4⁺ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.

This study examines the effectiveness of adaptive observation experiments using the ensemble transformation sensitivity (ETS) method to improve precipitation forecasts during heavy rainfall events in South China and the Sichuan Basin. High-resolution numerical models are employed to simulate adaptive observations. By identifying the sensitive areas of key weather system positions 42 hours before heavy rainfall events, the adaptive observations improve the prediction of jet streams, strong winds, and shear lines, which are essential for accurate heavy rainfall forecasting. This improvement is reflected in both the precipitation structure and location accuracy within the verification region. In South China, targeted observations enhance rainfall predictions by improving water vapor transport. In the Sichuan Basin, adaptive observations refine water vapor transport and adjust vortex dynamics. This research highlights the importance of accurately predicting shear lines and jet streams for forecasting heavy rainfall in these areas. Overall, this study found that adaptive observation enhances the precipitation forecast skills of the structure and location for heavy rainfall in South China and the Sichuan Basin, emphasizing their potential utility in operational numerical weather prediction.