Immune targeting of three independent suppressive pathways (TIGIT, PD-L1, TGFβ) provides significant antitumor efficacy in immune checkpoint resistant models.

Immune checkpoint blockade (ICB) therapy, while groundbreaking, must be improved to promote enhanced durable responses and to prevent the development of treatment-refractory disease. Cancer therapies that engage, enable, and expand the antitumor immune response will likely require rationally designed combination strategies. Targeting multiple immunosuppressive pathways simultaneously may provide additional therapeutic benefit over singular targeting.

From Immunogenic Cell Death to Immunogenic Modulation: Select Chemotherapy Regimens Induce a Spectrum of Immune-Enhancing Activities in the Tumor Microenvironment.

Cancer treatment has rapidly entered the age of immunotherapy, and it is becoming clear that the effective therapy of established tumors necessitates rational multi-combination immunotherapy strategies. But even in the advent of immunotherapy, the clinical role of standard-of-care chemotherapy regimens still remains significant and may be complementary to emerging immunotherapeutic approaches. Depending on dose, schedule, and agent, chemotherapy can induce immunogenic cell death, resulting in the release of tumor antigens to stimulate an immune response, or immunogenic modulation, sensitizing surviving tumor cells to immune cell killing.

Exploiting off-target effects of estrogen deprivation to sensitize estrogen receptor negative breast cancer to immune killing.

Background: There are highly effective treatment strategies for estrogen receptor (ER)+, progesterone receptor (PR)+, and HER2+ breast cancers; however, there are limited targeted therapeutic strategies for the 10%-15% of women who are diagnosed with triple-negative breast cancer. Here, we hypothesize that ER targeting drugs induce phenotypic changes to sensitize breast tumor cells to immune-mediated killing regardless of their ER status.

Methods: Real-time cell analysis, flow cytometry, qRT-PCR, western blotting, and multiplexed RNA profiling were performed to characterize ER+ and ER- breast cancer cells and to interrogate the phenotypic effects of ER targeting drugs.

Stay on Target: Reengaging Cancer Vaccines in Combination Immunotherapy.

Effective treatment of established tumors requires rational multicombination immunotherapy strategies designed to target all functions of the patient immune system and tumor immune microenvironment. While these combinations build on the foundation of successful immune checkpoint blockade antibodies, it is increasingly apparent that successful immunotherapy will also require a cancer vaccine backbone to engage the immune system, thereby ensuring that additional immuno-oncology agents will engage a tumor-specific immune response. This review summarizes ongoing clinical trials built upon the backbone of cancer vaccines and focusing on those clinical trials that utilize multicombination (3+) immuno-oncology agents.

Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable.

Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (i) a tumor antigen-targeting adenovirus-based vaccine (Ad-CEA) and an IL15 superagonist (N-803) to activate tumor-specific T cells, (ii) OX40 and GITR agonists to expand and enhance the activated effector populations, and (iii) an IDO inhibitor (IDOi) to enable effector-cell activity in the TME. Flow cytometry, T-cell receptor (TCR) sequencing, and RNA-sequencing (RNA-seq) analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated antitumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO.

Natural Born Killers: NK Cells in Cancer Therapy.

Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor (CAR) expressing T cells has gained FDA approval in hematologic malignancy. However, limited efficacy was observed using CAR-T therapy in solid tumors. Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner.

Overcoming hypoxia-induced functional suppression of NK cells.

Background: Natural killer (NK) cells are immune cells capable of killing virally infected cells and tumor cells without the need for antigen stimulation. Tumors, however, can create a suppressive microenvironment that decreases NK function. A feature of many tumors is hypoxia (low oxygen perfusion), which has been previously shown to decrease NK function.

Correction to: Immunotherapy Utilizing the Combination of Natural Killer- and Antibody Dependent Cellular Cytotoxicity (ADCC)-Mediating Agents with Poly (ADP-ribose) polymerase (PARP) Inhibition.

Following publication of the original article [1], an error was noted in the GAPDH in the western blot depicted in Figure 4b.

Immunotherapy utilizing the combination of natural killer- and antibody dependent cellular cytotoxicity (ADCC)-mediating agents with poly (ADP-ribose) polymerase (PARP) inhibition.

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations.

Impact of miR-140 Deficiency on Non-Alcoholic Fatty Liver Disease.

Scope: We have previously shown that loss of miR-140 has a pro-fibrotic effect in the mammary gland. This study aims to investigate whether miR-140 loss and obesity act synergistically to promote non-alcoholic fatty liver disease (NAFLD), and to identify the underlying mechanisms.

Methods And Results: Liver tissues were isolated from lean-fat-diet and high-fat-diet fed wild-type and miR-140 knockout mice.

Cellular, physiological and pathological aspects of the long non-coding RNA NEAT1.

Background: The majority of mammalian genomes have been found to be transcribed into non-coding RNAs. One category of non-coding RNAs is classified as long non-coding RNAs (lncRNAs) based on their transcript sizes larger than 200 nucleotides. Growing evidence has shown that lncRNAs are not junk transcripts and play regulatory roles in multiple aspects of biological processes.

Non-invasive detection of bladder cancer via expression-targeted gene delivery.

Background: Because of the time and expense associated with the procedures and possible distress to the patient, cystoscopy or other imaging techniques are typically not used for bladder cancer detection before symptoms become present. Alternatively, commercial assays for urinary tumor markers exist but are marred by low sensitivity and high cost. There is a need for a simple and sensitive means of tumor detection, such as via the analysis of urine.

The role of endothelial lipase in lipid metabolism, inflammation, and cancer.

Endothelial lipase (LIPG) plays a critical role in lipoprotein metabolism, cytokine expression, and the lipid composition of cells. Thus far, the extensive investigations of LIPG have focused on its mechanisms and involvement in metabolic syndromes such as atherosclerosis. However, recent developments have found that LIPG plays a role in cancer.

Tumor-associated myoepithelial cells promote the invasive progression of ductal carcinoma through activation of TGFβ signaling.

The normal myoepithelium has a tumor-suppressing nature and inhibits the progression of ductal carcinoma (DCIS) into invasive ductal carcinoma (IDC). Conversely, a growing number of studies have shown that tumor-associated myoepithelial cells have a tumor-promoting effect. Moreover, the exact role of tumor-associated myoepithelial cells in the DCIS-to-IDC development remains undefined.

Cancer stem cells and early stage basal-like breast cancer.

Ductal carcinoma (DCIS) is a category of early stage, non-invasive breast tumor defined by the intraductal proliferation of malignant breast epithelial cells. DCIS is a heterogeneous disease composed of multiple molecular subtypes including luminal, HER2 and basal-like types, which are characterized by immunohistochemical analyses and gene expression profiling. Following surgical and radiation therapies, patients with luminal-type, estrogen receptor-positive DCIS breast tumors can benefit from adjuvant endocrine-based treatment.

Loss of miR-140 is a key risk factor for radiation-induced lung fibrosis through reprogramming fibroblasts and macrophages.

Radiation-induced lung fibrosis (RILF) is a common side effect for patients with thoracic cancer receiving radiation therapy. RILF is characterized by excessive collagen deposition mediated by TGF-β1 and its downstream factor SMAD3, but the exact molecular mechanism leading to fibrosis is yet to be determined. The present study investigated the impact of miR-140 on RILF development.

Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis.

Radiation-induced lung fibrosis (RILF) is a common side effect of thoracic irradiation therapy and leads to high mortality rates after cancer treatment. Radiation injury induces inflammatory M1 macrophage polarization leading to radiation pneumonitis, the first stage of RILF progression. Fibrosis occurs due to the transition of M1 macrophages to the anti-inflammatory pro-fibrotic M2 phenotype, and the resulting imbalance of macrophage regulated inflammatory signaling.

A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation.

Human breast adipose tissue is a heterogeneous cell population consisting of mature white adipocytes, multipotent mesenchymal stem cells, committed progenitor cells, fibroblasts, endothelial cells, and immune cells. Dependent on external stimulation, adipose-derived stem cells differentiate along diverse lineages into adipocytes, chondrocytes, osteoblasts, fibroblasts, and myofibroblasts. It is currently not fully understood how a high-fat diet reprograms adipose-derived stem cells into myofibroblasts.

Dysregulation of the BRCA1/long non-coding RNA NEAT1 signaling axis contributes to breast tumorigenesis.

Dysregulation of long non-codng RNA (lncRNA) expression has been found to contribute to tumorigenesis. However, the roles of lncRNAs in BRCA1-related breast cancer remain largely unknown. In this study, we delineate the role of the novel BRCA1/lncRNA NEAT1 signaling axis in breast tumorigenesis.

Characterization of the CD49f+/CD44+/CD24- single-cell derived stem cell population in basal-like DCIS cells.

The molecular mechanisms responsible for the Ductal Carcinoma in Situ (DCIS)-Invasive Ductal Carcinoma (IDC) transition have yet to be elucidated. Due to the lack of molecularly targeted therapies, basal-like DCIS has a high risk of recurrence and progression to invasive and metastatic cancers. In this study, by applying a novel single-cell clonogenic approach with the CD49f+/CD44+/CD24- surface markers, we characterized the aggressive clones that have enhanced self-renewal, migratory and invasive capacities derived from a human DCIS model cell line MCF10DCIS.

Noncoding RNAs in breast cancer.

The mammalian transcriptome has recently been revealed to encompass a large number of noncoding RNAs (ncRNAs) that play a variety of important regulatory roles in gene expression and other biological processes. MicroRNAs (miRNAs), the best studied of the short noncoding RNAs (sncRNAs), have been extensively characterized with regard to their biogenesis, function and importance in tumorigenesis. Another class of sncRNAs called piwi-interacting RNAs (piRNAs) has also gained attention recently in cancer research owing to their critical role in stem cell regulation.

MicroRNA 140 Promotes Expression of Long Noncoding RNA NEAT1 in Adipogenesis.

More than 40% of the U.S. population are clinically obese and suffer from metabolic syndrome with an increased risk of postmenopausal estrogen receptor-positive breast cancer.

NRF2/miR-140 signaling confers radioprotection to human lung fibroblasts.

Breast and lung cancer patients who are treated with radiotherapy often have severe side effects, including radiation-induced lung damage and secondary cancers. Activation of the NRF2 pathway is a well-known mechanism that protects cells against radiation induced oxidative stress, but its role in radiation-induced lung damage is not well understood. Using human lung fibroblasts (HLFs) we found that ionizing radiation (IR) leads to BRCA1-dependent activation of NRF2 through the inhibition of KEAP1 function, promoting the nuclear accumulation of NRF2, and activating critical radioprotective mechanisms.

Adipocyte activation of cancer stem cell signaling in breast cancer.

Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment, have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6 (IL-6) have a paracrine effect on breast cancer cells.