Phase Ib pharmacodynamic study of the MNK inhibitor Tomivosertib (eFT508) combined with paclitaxel in patients with refractory metastatic breast cancer.

Purpose: Preclinical data motivate clinical evaluation of inhibitors of mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2). We conducted a phase 1b clinical trial to study target engagement and safety of tomivosertib, a MNK1/2 inhibitor, alone and in combination with paclitaxel.

Methods: Eligible patients had metastatic breast cancer resistant to standard of care treatments.

Maternal Innate Immune Reprogramming After Complicated Pregnancy.

Problem: Preeclampsia (PE) and fetal growth restriction (FGR) are often associated with maternal inflammation and an increased risk of cardiovascular and metabolic disease in the affected mothers. The mechanism responsible for this increased risk of subsequent disease may involve reprogramming of innate immune cells, characterized by epigenetic modifications.

Method Of Study: Circulating monocytes from women with PE, FGR, or uncomplicated pregnancies (control) were isolated before labor.

Secondary Analysis of Interstitial Cystitis/Bladder Pain Syndrome Patients Enrolled in a Recurrent Urinary Tract Infection Prevention Study Provides a Novel Paradigm for Etio-Pathogenesis and Practical Management of This Infection Phenotype.

Introduction: A subset of interstitial cystitis/bladder pain syndrome (IC/BPS) patients experience recurrent urinary tract infection (rUTI) associated with symptom flares. Recurrent UTI subjects with associated IC/BPS were enrolled in the first North American early clinical experience trial evaluating a new sublingual UTI preventative vaccine, MV140. It has been shown that women with rUTI develop an imbalance in the T helper 1 and 2 (Th2 over-expression) in the bladder mucosa.

Imaging Mass Cytometry in Immuno-Oncology.

In situ profiling of the tumor-immune microenvironment (TiME) requires the ability to co-localize and detect multiple proteins simultaneously. Imaging mass cytometry (IMC), using the Hyperion™ imaging system is a novel multiplex imaging modality that currently enables detection of up to 50 markers on fixed tissues at subcellular resolution and thus has the potential to inform both pre-clinical and clinical research by providing investigators with spatially resolved information about the TiME. Here we provide an overview of the IMC workflow from sample fixation to analysis, with a focus on multiplex panel design and tissue staining.

Cross-Generational Impact of Innate Immune Memory Following Pregnancy Complications.

Pregnancy complications can have long-term negative effects on the health of the affected mothers and their children. In this review, we highlight the underlying inflammatory etiologies of common pregnancy complications and discuss how aberrant inflammation may lead to the acquisition of innate immune memory. The latter can be described as a functional epigenetic reprogramming of innate immune cells following an initial exposure to an inflammatory stimulus, ultimately resulting in an altered response following re-exposure to a similar inflammatory stimulus.

Automated Cell Phenotyping for Imaging Mass Cytometry.

Imaging mass cytometry (IMC) is a new advancement in tissue imaging that is quickly gaining wider usage since its recent launch. It improves upon current tissue imaging methods by allowing for a significantly higher number of proteins to be imaged at once on a single tissue slide. For most analyses of IMC data, determining the phenotype of each cell is a crucial step.

Aberrant inflammation in rat pregnancy leads to cardiometabolic alterations in the offspring and intrauterine growth restriction in the F2 generation.

Children of women with pre-eclampsia have increased risk of cardiovascular (CV) and metabolic disease in adult life. Furthermore, the risk of pregnancy complications is higher in daughters born to women affected by pre-eclampsia than in daughters born after uncomplicated pregnancies. While aberrant inflammation contributes to the pathophysiology of pregnancy complications, including pre-eclampsia, the contribution of maternal inflammation to subsequent risk of CV and metabolic disease as well as pregnancy complications in the offspring remains unclear.

TITAN: An end-to-end data analysis environment for the Hyperion™ imaging system.

Imaging Mass Cytometry (IMC) is a powerful high-throughput technique enabling resolution of up to 37 markers in a single fixed tissue section while also preserving in situ spatial relationships. Currently, IMC processing and analysis necessitates the use of multiple different software, labour-intensive pipeline development, different operating systems and knowledge of bioinformatics, all of which are a barrier to many potential users. Here we present TITAN - an open-source, single environment, end-to-end pipeline that can be utilized for image visualization, segmentation, analysis and export of IMC data.

The MNK1/2-eIF4E Axis Supports Immune Suppression and Metastasis in Postpartum Breast Cancer.

Breast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2-eIF4E axis promotes translation of prometastatic mRNAs in tumor cells, but its role in modulating the function of nontumor cells in the PPBC microenvironment has not been explored.

Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy.

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis.

Postpartum alterations following inflammation in rat pregnancy: a discovery proteomic analysis.

Women with a history of preeclampsia have an increased risk of subsequent cardiovascular and metabolic disease. While aberrant inflammation during pregnancy is associated with the development of preeclampsia, whether maternal inflammation increases the risk of disease later in life is unclear. Using a rat model we determined whether aberrant inflammation in pregnancy alters the levels of plasma proteins associated with cardiovascular and metabolic disease risk in the postpartum period.

Innate immune memory is associated with increased disease-free survival in bladder cancer patients treated with bacillus Calmette-Guérin.

Introduction: While studies suggest that innate immune memory acquired by circulating monocytes may mediate the benefit of bacillus Calmette-Guérin (BCG) in the treatment of patients with high-risk non-muscle-invasive bladder cancer (NMIBC), prospective studies are lacking. Innate immune memory is defined by enhanced release of pro-inflammatory cytokines by innate immune cells following a secondary challenge with pattern recognition receptor (PRR) ligands.

Methods: Peripheral blood monocytes isolated from 33 patients with intermediate- or high-risk NMIBC before and after two or five induction BCG instillations were stimulated with the PRR ligand lipopolysaccharide (LPS).

Hypoxia-Induced Resistance to Chemotherapy in Cancer.

A major barrier to the successful management of cancer is the development of resistance to therapy. Chemotherapy resistance can either be an intrinsic property of malignant cells developed prior to therapy, or acquired following exposure to anti-cancer drugs. Given the impact of drug resistance to the overall poor survival of cancer patients, there is an urgent need to better understand the molecular pathways regulating this malignant phenotype.

Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets.

The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages.

Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy.

Complement is a critical component of humoral immunity implicated in cancer development; however, its biological contributions to tumorigenesis remain poorly understood. Using the K14-HPV16 transgenic mouse model of squamous carcinogenesis, we report that urokinase (uPA) macrophages regulate C3-independent release of C5a during premalignant progression, which in turn regulates protumorigenic properties of C5aR1 mast cells and macrophages, including suppression of CD8 T cell cytotoxicity. Therapeutic inhibition of C5aR1 via the peptide antagonist PMX-53 improved efficacy of paclitaxel chemotherapy associated with increased presence and cytotoxic properties of CXCR3 effector memory CD8 T cells in carcinomas, dependent on both macrophage transcriptional programming and IFNγ.

Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy ( = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders.

Inflammation-induced fetal growth restriction in rats is associated with increased placental HIF-1α accumulation.

Introduction: Hypoxia-inducible factor 1-alpha (HIF-1α) is the oxygen-sensitive subunit of the transcription factor HIF-1, and its expression is increased in placentas from pregnancies complicated by pre-eclampsia (PE). Fetal growth restriction (FGR) and PE often share a common pathophysiology; however, it is unknown whether increased placental HIF-1α occurs in FGR. We previously demonstrated that aberrant maternal inflammation in rats resulted in altered utero-placental perfusion and FGR, both of which were prevented by administration of the nitric oxide mimetic glyceryl trinitrate (GTN).

Moderate Exercise Attenuates Lipopolysaccharide-Induced Inflammation and Associated Maternal and Fetal Morbidities in Pregnant Rats.

Fetal growth restriction (FGR) and coagulopathies are often associated with aberrant maternal inflammation. Moderate-intensity exercise during pregnancy has been shown to increase utero-placental blood flow and to enhance fetal nutrition as well as fetal and placental growth. Furthermore, exercise is known to reduce inflammation.

Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis.

The ability of tumor cells to avoid immune destruction (immune escape) as well as their acquired resistance to anti-cancer drugs constitute important barriers to the successful management of cancer. Interaction between the Programmed Death Ligand 1 (PD-L1) on the surface of tumor cells with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes leads to inactivation of these immune effectors and, consequently, immune escape. Here we show that the PD-1/PD-L1 axis also leads to tumor cell resistance to conventional chemotherapeutic agents.

Immune response to cancer therapy: mounting an effective antitumor response and mechanisms of resistance.

Chemotherapy and radiotherapy have been extensively used to eradicate cancer based on their direct cytocidal effects on rapidly proliferating tumor cells. Accumulating evidence indicates that these therapies also dramatically affect resident and recruited immune cells that actively support tumor growth. We now appreciate that mobilization of effector CD8 T cells enhances efficacy of chemotherapy and radiotherapy; remarkable clinical advances have been achieved by blocking regulatory programs limiting cytotoxic CD8 T cell activity .

Myeloid Cells as Targets for Therapy in Solid Tumors.

It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited "host" cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation.