TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids.

Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. In this study, we examined the activity of B7-H3-directed CAR T cells (B7-H3.

Potent antitumor activity of a designed interleukin-21 mimic.

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report a IL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and in human melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity.

Overcoming Resistance Mechanisms to Melanoma Immunotherapy.

The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients.

Substance-Use Disorders in Critically Ill Patients: A Narrative Review.

Substance-use disorders (SUDs) represent a major public health concern. The increased prevalence of SUDs within the general population has led to more patients with SUD being admitted to intensive care units (ICUs) for an SUD-related condition or with SUD as a relevant comorbidity. Multiprofessional providers of critical care should be familiar with these disorders and their impact on critical illness.

N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma.

High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines.

Emerging roles of TBK1 in cancer immunobiology.

TANK-binding kinase 1 (TBK1) is a versatile serine/threonine protein kinase with established roles in innate immunity, metabolism, autophagy, cell death, and inflammation. While best known for its role in regulating innate immunity, TBK1 has emerged as a cancer cell-intrinsic immune evasion gene by virtue of its role in modulating cellular responses to inflammatory signals emanating from the immune system. Beyond its effect on cancer cells, TBK1 appears to regulate lymphoid and myeloid cells in the tumor immune microenvironment.

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy.

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD) catabolism, is highly expressed in exhausted CD8 T cells in melanoma and is associated with ICB resistance.

Mesothelin CAR T Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and its Stroma.

Purpose: Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated by cancer-associated fibroblasts (CAF), which may contribute to the limited efficacy of mesothelin-directed CAR T cells in early-phase clinical trials. To provide a more favorable TME for CAR T cells to target pancreatic ductal adenocarcinoma (PDAC), we generated T cells with an antimesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAF through fibroblast activation protein (FAP) and engages T cells through CD3 (termed mesoFAP CAR-TEAM cells).

Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), two clinically relevant targets for the immunotherapy of cancer, are negative regulators of T-cell activation and migration. Optimizing the therapeutic response to CTLA-4 and PD-1 blockade calls for a more comprehensive insight into the coordinated function of these immune regulators. Mathematical modeling can be used to elucidate nonlinear tumor-immune interactions and highlight the underlying mechanisms to tackle the problem.

Going with the Flow: Modeling the Tumor Microenvironment Using Microfluidic Technology.

Recent advances in cancer immunotherapy have led a paradigm shift in the treatment of multiple malignancies with renewed focus on the host immune system and tumor-immune dynamics. However, intrinsic and acquired resistance to immunotherapy limits patient benefits and wider application. Investigations into the mechanisms of response and resistance to immunotherapy have demonstrated key tumor-intrinsic and tumor-extrinsic factors.

Mutant IDH Inhibits IFNγ-TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma.

Unlabelled: Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase.

Mapping the immune environment in clear cell renal carcinoma by single-cell genomics.

Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45 lymphoid and myeloid cells in matched tumor and blood from three patients with ccRCC. We also included 11,367 immune cells from four other individuals derived from the kidney and peripheral blood to facilitate the identification and assessment of ccRCC-specific differences.

Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade.

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing.

Targeting TANK-binding kinase 1 (TBK1) in cancer.

Introduction: TANK-binding kinase 1 (TBK1) is a Ser/Thr kinase with a central role in coordinating the cellular response to invading pathogens and regulating key inflammatory signaling cascades. While intact TBK1 signaling is required for successful anti-viral signaling, dysregulated TBK1 signaling has been linked to a variety of pathophysiologic conditions, including cancer. Several lines of evidence support a role for TBK1 in cancer pathogenesis, but the specific roles and regulation of TBK1 remain incompletely understood.

Treatment of Advanced Melanoma in 2020 and Beyond.

The melanoma field has seen an unprecedented set of clinical advances over the past decade. Therapeutic efficacy for advanced or metastatic melanoma went from being one of the most poorly responsive to one of the more responsive. Perhaps most strikingly, the advances that transformed management of the disease are based upon modern mechanism-based therapeutic strategies.

Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma.

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors.