Immune-molecular interactions in high-grade serous ovarian cancer distinguish long-term survivors.

The approach and efficacy of treatments for high-grade serous carcinoma (HGSC) of the ovary have changed little in decades. Although numerous studies demonstrated immune infiltration as frequent and prognostically beneficial, clinical trials of immunotherapies have generated benefit in fewer than 15% of patients. In this issue of the JCI, Nelson and colleagues compiled 1,233 HGSC samples from patients across four continents and compared the molecular and immunologic features that associate with long-term survival (greater than 10 years).

Mitochondrial DNA levels in perfusate and bile during normothermic machine correspond with donor liver quality.

normothermic machine perfusion (NMP) preserves donor organs and permits real-time assessment of allograft health, but the most effective indicators of graft viability are uncertain. Mitochondrial DNA (mtDNA), released consequent to traumatic cell injury and death, including the ischemia-reperfusion injury inherent in transplantation, may meet the need for a biomarker in this context. We describe a real time PCR-based approach to assess cell-free mtDNA during NMP as a universal biomarker of allograft quality.

Improved overall survival in patients with high-grade serous ovarian cancer is associated with CD16a+ immunologic neighborhoods containing NK cells, T cells and macrophages.

Background: For patients with high grade serous carcinoma of the ovary (HGSC), survival rates have remained static for the last half century. Despite the presence of tumor mutations and infiltration of immune cells, existing immunotherapies have achieved little success against HGSC. These observations highlight a gap in the understanding of how the immune system functions and interacts within HGSC tumors.

Killer instincts: natural killer cells as multifactorial cancer immunotherapy.

Natural killer (NK) cells integrate heterogeneous signals for activation and inhibition using germline-encoded receptors. These receptors are stochastically co-expressed, and their concurrent engagement and signaling can adjust the sensitivity of individual cells to putative targets. Against cancers, which mutate and evolve under therapeutic and immunologic pressure, the diversity for recognition provided by NK cells may be key to comprehensive cancer control.

BioCanRx Summit for Cancer Immunotherapy 2022 Proceedings.

From 19 to 21 November 2022, BioCanRx held its first post-pandemic in-person Summit for Cancer Immunotherapy in Montreal, Canada. The meeting was well attended by patients, trainees, researchers, clinicians, and industry professionals, who came together to discuss the current state and future of biotherapeutics for cancer in Canada and beyond. Three plenaries, three keynote speakers, a lively debate, and panel discussions, together with poster sessions and a social event, made the event memorable and productive.

Predicting Early Graft Dysfunction and Mortality After Liver Transplant Using the De Ritis Ratio.

Background: Predicting complications after liver transplantation (LT) remains challenging. We propose incorporating the De Ritis ratio (DRR), a widely known parameter of liver dysfunction, into current or future scoring models to predict early allograft dysfunction (EAD) and mortality after LT.

Methods: A retrospective chart review was conducted on 132 adults receiving a deceased donor LT from April 2015 to March 2020 and their matching donors.

Changing liver utilization and discard rates in clinical transplantation in the ex-vivo machine preservation era.

Liver transplantation is a well-established treatment for many with end-stage liver disease. Unfortunately, the increasing organ demand has surpassed the donor supply, and approximately 30% of patients die while waiting for a suitable liver. Clinicians are often forced to consider livers of inferior quality to increase organ donation rates, but ultimately, many of those organs end up being discarded.

Perioperative oncolytic virotherapy to counteract surgery-induced immunosuppression and improve outcomes in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a high fatality cancer with one of the worst prognoses in solid tumors. Most patients present with late stage, metastatic disease and are not eligible for potentially curative surgery. Despite complete resection, the majority of surgical patients will recur within the first two years following surgery.

The Canadian Society for Immunology's 34th annual meeting 2022: symposia minireview.

The Canadian Society for Immunology 2022 Annual Meeting (June 17-20, 2022) brought together immunologists from across the country to discuss current topics and cutting-edge research in immunology. Here we highlight the published work presented during three thematic symposia (1) Immune Development and Layered Immunity; (2) Primary Immune Deficiencies from Thymic Developmental Defects to Dysregulation and Inflammation; and (3) Opposing Inflammatory and Suppressive Regulation of Anti-Tumor Immunity.

Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue.

Mitochondrial damage-associated molecular patterns (mitoDAMPs) are released from cells dying uncontrolled, non-apoptotic deaths, usually secondary to disease or trauma. Here, we describe preparation of mitoDAMPs from mouse liver, but this protocol can be adapted for preparation of mitoDAMPs from other species and tissues. Tissues are dissociated and then processed to isolate mitochondria.

Manual Immunofluorescence of Formalin-Fixed Paraffin-Embedded Human Tumor Tissues.

Immunofluorescence (IF) of tumor tissues has become a key tool in the study of cancer. With a wide variety of formalin-fixed paraffin-embedded (FFPE) preserved tissues available, there are possibilities to assess large cohorts using archived tissue which may have archived associated clinical outcomes. Although best practice guidelines for the assessment of tissues have been published, a standardized method for immunofluorescence of FFPE tumor tissues is elusive.

Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation.

Tissue damage leads to loss of cellular and mitochondrial membrane integrity and release of damage-associated molecular patterns, including those of mitochondrial origin (mitoDAMPs). Here, we describe the lymphocyte response to mitoDAMPs. Using primary cells from mice and human donors, we demonstrate that natural killer (NK) cells and T cells adopt regulatory phenotypes and functions in response to mitoDAMPs.

Natural Killer Cells: the Missing Link in Effective Treatment for High-Grade Serous Ovarian Carcinoma.

Ovarian cancer (OC), especially high-grade serous cancer (HGSC), is a highly heterogeneous malignancy with limited options for curative treatment and a high frequency of relapse. Interactions between OC and the immune system may permit immunoediting and immune escape, and current standard of care therapies can influence immune cell infiltration and function within the tumor microenvironment. Natural killer (NK) cells are involved in cancer immunosurveillance and immunoediting and can be activated by therapy, but deliberate approaches to maximize NK cell reactivity for treatment of HGSC are in their infancy.

NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis.

The immune landscape of a tumor is highly connected to patient prognosis and response to treatment, but little is known about how natural killer (NK) cells predict overall survival (OS) among patients with solid tumors. We present the first meta-analysis on NK cell infiltration into solid tumors as a prognostic indicator for OS, considering cancer types independently, and together. Samples were collected from 1973 to 2016 with results published between 1989 and 2020.

Publisher Correction: Novel multiplex PCR-SSP method for centromeric KIR allele discrimination.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

The Evolutionary Arms Race between Virus and NK Cells: Diversity Enables Population-Level Virus Control.

Viruses and natural killer (NK) cells have a long co-evolutionary history, evidenced by patterns of specific NK gene frequencies in those susceptible or resistant to infections. The killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) ligands together form the most polymorphic receptor-ligand partnership in the human genome and govern the process of NK cell education. The and genes segregate independently, thus creating an array of reactive potentials within and between the NK cell repertoires of individuals.

Naturally Killing the Silent Killer: NK Cell-Based Immunotherapy for Ovarian Cancer.

Ovarian cancer (OC) is diagnosed in ~22,000 women in the US each year and kills 14,000 of them. Often, patients are not diagnosed until the later stages of disease, when treatment options are limited, highlighting the urgent need for new and improved therapies for precise cancer control. An individual's immune function and interaction with tumor cells can be prognostic of the response to cancer treatment.

Novel Approach to Cell Surface Discrimination Between KIR2DL1 Subtypes and KIR2DS1 Identifies Hierarchies in NK Repertoire, Education, and Tolerance.

Cumulative activating and inhibitory receptor signaling controls the functional output of individual natural killer (NK) cells. Investigation of how competing signals impact response, however, has been hampered by the lack of available antibodies capable of distinguishing inhibitory and activating receptors with highly homologous ectodomains. Utilizing a novel combination of monoclonal antibodies with specificity for discrete inhibitory KIR2DL1 and activating KIR2DS1 allotypes found among 230 healthy donors, we investigated allele-specific receptor expression and function driven by and alleles.

Novel multiplex PCR-SSP method for centromeric KIR allele discrimination.

Allelic diversity of the KIR2DL receptors drive differential expression and ligand-binding affinities that impact natural killer cell function and patient outcomes for diverse cancers. We have developed a global intermediate resolution amplification-refractory mutation system (ARMS) PCR-SSP method for distinguishing functionally relevant subgroups of the KIR2DL receptors, as defined by phylogenetic study of the protein sequences. Use of the ARMS design makes the method reliable and usable as a kit, with all reactions utilizing the same conditions.

Natural killer cell education in human health and disease.

Natural killer (NK) cells maintain immune homeostasis by detecting and eliminating damaged cells. Simultaneous activating and inhibitory input are integrated by NK cells, with the net signal prompting cytotoxicity and cytokine production, or inhibition. Chief among the inhibitory ligands for NK cells are 'self' human leukocyte antigen (HLA) molecules, which are sensed by killer immunoglobulin-like receptors (KIR).

Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned.

The functional capacities of natural killer (NK) cells differ within and between individuals, reflecting considerable genetic variation. 'Licensing/arming', 'disarming', and 'tuning' are models that have been proposed to explain how interactions between MHC class I molecules and their cognate inhibitory receptors - Ly49 in mice and KIR in humans - 'educate' NK cells for variable reactivity and sensitivity to inhibition. In this review we discuss recent progress toward understanding the genetic, epigenetic, and molecular features that titrate NK effector function and inhibition, and the impact of variable NK cell education on human health and disease.

Genetic Mutations and Epigenetic Modifications: Driving Cancer and Informing Precision Medicine.

Cancer treatment is undergoing a significant revolution from "one-size-fits-all" cytotoxic therapies to tailored approaches that precisely target molecular alterations. Precision strategies for drug development and patient stratification, based on the molecular features of tumors, are the next logical step in a long history of approaches to cancer therapy. In this review, we discuss the history of cancer treatment from generic natural extracts and radical surgical procedures to site-specific and combinatorial treatment regimens, which have incrementally improved patient outcomes.

KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation.

Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells-upregulated in the post-HCT environment-signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity.