Suppressing PD-L1 Expression via AURKA Kinase Inhibition Enhances Natural Killer Cell-Mediated Cytotoxicity against Glioblastoma.

Immunotherapies have shown significant promise as an impactful strategy in cancer treatment. However, in glioblastoma multiforme (GBM), the most prevalent primary brain tumor in adults, these therapies have demonstrated lower efficacy than initially anticipated. Consequently, there is an urgent need for strategies to enhance the effectiveness of immune treatments.

Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens.

Single-nucleotide variants (SNVs) in key T cell genes can drive clinical pathologies and could be repurposed to improve cellular cancer immunotherapies. Here, we perform massively parallel base-editing screens to generate thousands of variants at gene loci annotated with known or potential clinical relevance. We discover a broad landscape of putative gain-of-function (GOF) and loss-of-function (LOF) mutations, including in PIK3CD and the gene encoding its regulatory subunit, PIK3R1, LCK, SOS1, AKT1 and RHOA.

Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis.

From patient tissue correlates to molecular mechanisms of cancer immune evasion: the emerging role of CD58 and PD-L1 co-regulation via CMTM6.

Immune evasion is a hallmark of cancer, yet the underlying mechanisms are often unknown in many patients. Using single-cell transcriptomics analysis, we previously identified the co-stimulator CD58 as part of a cancer cell-intrinsic immune checkpoint resistance signature in patient melanoma tissue. We subsequently validated CD58 loss as a driver of immune evasion using a patient-derived co-culture model of cancer and cytotoxic tumor-infiltrating lymphocytes in a pooled single-cell perturbation experiment, where we additionally observed concurrent upregulation of PD-L1 protein expression in melanoma cells with CD58 loss.

KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response.

The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.

The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization.

Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators.

Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate master regulators (MRs) as mechanistic determinants of TI-Treg transcriptional state.

KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response.

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways.

Tumor cell intrinsic Toll-like receptor 4 signaling promotes melanoma progression and metastatic dissemination.

Most melanoma-associated deaths result from the early development of metastasis. Toll-like receptor 4 (TLR4) expression on nontumor cells is well known to contribute to tumor development and metastatic progression. The role of TLR4 expression on tumor cells however is less well understood.

The myeloid cell type I IFN system promotes antitumor immunity over pro-tumoral inflammation in cancer T-cell therapy.

Objectives: Type I interferons are evolutionally conserved cytokines, with broad antimicrobial and immunoregulatory functions. Despite well-characterised role in spontaneous cancer immunosurveillance, the function of type I IFNs in cancer immunotherapy remains incompletely understood.

Methods: We utilised genetic mouse models to explore the role of the type I IFN system in CD8 T-cell immunotherapy targeting the melanocytic lineage antigen gp100.

A molecular single-cell lung atlas of lethal COVID-19.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19.

A single-cell landscape of high-grade serous ovarian cancer.

Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations.

Authorship: From credit to accountability - Reflections from the Editors' network.

The Editors' Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability.

Authorship: From credit to accountability. Reflections from the Editors' Network.

The Editors' Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability.

Authorship: From Credit to Accountability Reflections From the Editors´ Network.

The Editors´ Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability.

Authorship: from credit to accountability. Reflections from the Editors' Network.

The Editors' Network of the European Society of Cardiology provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability.

Authorship: from credit to accountability. Reflections from the Editors' Network.

The Editors' Network of the European Society of Cardiology provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability.