Immune Checkpoint Inhibitor-Associated Cutaneous Adverse Events: Mechanisms of Occurrence.

Immunotherapy, particularly that based on blocking checkpoint proteins in many tumors, including melanoma, Merkel cell carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast (TNB cancer), renal cancer, and gastrointestinal and endometrial neoplasms, is a therapeutic alternative to chemotherapy. Immune checkpoint inhibitor (ICI)-based therapies have the potential to target different pathways leading to the destruction of cancer cells. Although ICIs are an effective treatment strategy for patients with highly immune-infiltrated cancers, the development of different adverse effects including cutaneous adverse effects during and after the treatment with ICIs is common.

Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial.

We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics.

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Current Treatment Paradigm and Approach to Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common forms of primary liver cancer worldwide. Herein, we present a review article that provides a broad overview of the current landscape of HCC, including the etiology, potential risk factors, and molecular pathways that can serve as potential therapeutic targets. The risk factors tend to vary depending on the geographic distribution; hepatitis B-induced cirrhosis and HCC occur more frequently in Asia and Sub-Saharan Africa, whereas metabolic disorders are the culprits in Western Europe and the Americas.

SMAC-armed oncolytic virotherapy enhances the anticancer activity of PD1 blockade by modulating PANoptosis.

Background: Oncolytic viruses (OVs) are increasingly recognized as promising tools for cancer therapy, as they selectively infect and destroy tumor cells while leaving healthy cells unharmed. Despite considerable progress, the limited therapeutic efficacy of OV-based virotherapy continues to be a significant challenge in cancer treatment.

Methods: The SMAC/DIABLO gene was inserted into the genome of vesicular stomatitis virus (VSV) to generate VSV-S.

ANXA10 sensitizes microsatellite instability-high colorectal cancer to anti-PD-1 immunotherapy via assembly of HLA-DR dimers by regulating CD74.

Background: Microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) patients are the dominant population in immune checkpoint blockade treatments, while more than half of them could not benefit from single-agent immunotherapy. We tried to identify the biomarker of MSI-H CRC and explore its role and mechanism in anti-PD-1 treatments. Tumor-specific MHC-II was linked to a better response to anti-PD-1 in MSI-H CRC and CD74 promoted assembly and transport of HLA-DR dimers.

Acidic pH can attenuate immune killing through inactivation of perforin.

Cytotoxic lymphocytes are crucial to our immune system, primarily eliminating virus-infected or cancerous cells via perforin/granzyme killing. Perforin forms transmembrane pores in the plasma membrane, allowing granzymes to enter the target cell cytosol and trigger apoptosis. The prowess of cytotoxic lymphocytes to efficiently eradicate target cells has been widely harnessed in immunotherapies against haematological cancers.

Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma.

Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF).

Enhancing immunotherapy efficacy in colorectal cancer: targeting the FGR-AKT-SP1-DKK1 axis with DCC-2036 (Rebastinib).

This research demonstrates that DCC-2036 (Rebastinib), a potent third-generation tyrosine kinase inhibitor (TKI), effectively suppresses tumor growth in colorectal cancer (CRC) models with functional immune systems. The findings underscore the capacity of DCC-2036 to enhance both the activation and cytotoxic functionality of CD8 T cells, which are crucial for facilitating anti-tumor immune responses. Through comprehensive multi-omics investigations, significant shifts in both gene and protein expression profiles were detected, notably a marked decrease in DKK1 levels.

Concomitant antihistamine administration is associated with improved survival outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with atezolizumab. Analysis of individual participant data from IMvigor210 and IMvigor211.

Objectives: Survival outcomes of patients with metastatic urothelial carcinoma (mUC) are still suboptimal and strategies to enhance response to immune-oncology (IO) compounds are under scrutiny. In preclinical studies, it has been demonstrated that antihistamines may reverse macrophage immunosuppression, reactivate T cell cytotoxicity, and enhance the immunotherapy response. We aimed to evaluate the role of concomitant antihistamines administration on oncological outcomes among patients with mUC.

Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome.

Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up.

Application of tumor organoids simulating the tumor microenvironment in basic and clinical research of tumor immunotherapy.

Immunotherapy has led to groundbreaking advances in anti-tumor treatment, yet significant clinical challenges remain such as the low proportion of beneficiaries and the lack of effective platforms for predicting therapeutic response. Organoid technology provides a novel solution to these issues. Organoids are three-dimensional tissue cultures derived from adult stem cells or pluripotent stem cells that closely replicate the structural and biological characteristics of native organs, demonstrating particularly strong potential in modeling the tumor microenvironment (TME).

The analysis of molecular classification of pulmonary neuroendocrine tumors and relationship between YAP1 and efficacy.

A novel molecular classification for small cell lung cancer (SCLC) has been established utilizing the transcription factors achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). This classification was predicated on the transcription factors. Conversely, there is a paucity of information regarding the distribution of these markers in other subtypes of pulmonary neuroendocrine tumors (PNET).

Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are one of the key immunosuppressive components in the tumor microenvironment (TME) and contribute to tumor development, progression, and resistance to cancer immunotherapy. Several reagents targeting TAMs have been tested in preclinical and clinical studies, but they have had limited success. Here, we show that a unique reagent, FF-10101, exhibited a sustained inhibitory effect against colony-stimulating factor 1 receptor by forming a covalent bond and reduced immunosuppressive TAMs in the TME, which led to strong antitumor immunity.

Navigating the landscape of neoadjuvant immunotherapy for NSCLC: progress and controversies.

Recently, attention has increasingly centered on non-small-cell lung cancer (NSCLC) with immune checkpoint inhibitors application. Numerous clinical studies have underscored the potential of immunotherapy in treating resectable NSCLC, highlighting its role in improving patient outcomes. However, despite these promising results, there is ongoing debate regarding the efficacy of immunological combination therapy strategies, the prevalence of treatment-related side effects, the identification of predictive biomarkers, and various other challenges within the neoadjuvant context.

Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy.

The advent of immunotherapy represents a significant breakthrough in cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 demonstrating remarkable therapeutic efficacy. However, patient responses to immunotherapy vary significantly, with immunosuppression within the tumor microenvironment (TME) being a critical factor influencing this variability. Immunosuppression plays a pivotal role in regulating cancer progression, metastasis, and reducing the success rates of immunotherapy.

Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing.

Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing identifies rare populations that express specific marker transcript combinations, traditional flow sorting requires cell surface markers with high-fidelity antibodies, limiting our ability to interrogate these populations. In addition, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers.

A vision-language foundation model for precision oncology.

Clinical decision-making is driven by multimodal data, including clinical notes and pathological characteristics. Artificial intelligence approaches that can effectively integrate multimodal data hold significant promise in advancing clinical care. However, the scarcity of well-annotated multimodal datasets in clinical settings has hindered the development of useful models.

Society for Immunotherapy of Cancer: updates and best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) image analysis and data sharing.

Objectives: Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force.

The pathway alteration load is a pan-cancer determinant of outcome of targeted therapies: results from the Drug Rediscovery Protocol (DRUP).

Background: Many patients with cancer exhibit primary or rapid secondary resistance to targeted therapy (TT). We hypothesized that a higher number of altered oncogenic signaling pathways [pathway alteration load (PAL)] would reduce the benefit of TT which only intervenes in one pathway. This hypothesis was tested in the Drug Rediscovery Protocol (DRUP).

Polyfunctional CD8CD226RUNX2 effector T cells are diminished in advanced stages of chronic lymphocytic leukemia.

CD8 T cells, a subset of T cells identified by the surface glycoprotein CD8, particularly those expressing the co-stimulatory molecule CD226, play a crucial role in the immune response to malignancies. However, their role in chronic lymphocytic leukemia (CLL), an immunosuppressive disease, has not yet been explored. We studied 64 CLL patients and 25 age- and sex-matched healthy controls (HCs).

Generation of effective and specific human TCRs against tumor/testis antigen NY-ESO-1 in mice with humanized T cell recognition system.

Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1 restricted to HLA-A*02:01.

Spatial heterogeneity of the hepatocellular carcinoma microenvironment determines the efficacy of immunotherapy.

Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential.

Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment.

Background: Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios.

Methods: Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses.

Disruption of tumor-intrinsic PGAM5 increases anti-PD-1 efficacy through the CCL2 signaling pathway.

Background: Immunosuppressive phenotype compromised immunotherapy efficacy of hepatocellular carcinoma. Tumor cells intrinsic mitochondria dynamics could pass effects on the extracellular microenvironment through mtDNA stress. PGAM5 anchors at mitochondria and regulates mitochondria functions.