-
International Journal of Molecular... Apr 2019Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic liver injury, hepatic inflammation, and fibrosis. Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) are key players in liver fibrogenesis and hepatocarcinogenesis, respectively. CAFs, which probably derive from HSCs, activate into extracellular matrix (ECM)-producing myofibroblasts and crosstalk with cancer cells to affect tumor growth and invasion. In this review, we describe the different components which form the HCC premalignant microenvironment (PME) and the tumor microenvironment (TME), focusing on the liver fibrosis process and the biology of CAFs. We will describe the CAF-dependent mechanisms which have been suggested to promote hepatocarcinogenesis, such as the alteration of ECM, CAF-dependent production of cytokines and angiogenic factors, CAF-dependent reduction of immuno-surveillance, and CAF-dependent promotion of epithelial-mesenchymal transition (EMT). New knowledge of the fibrosis process and the role of CAFs in HCC may pave the way for new therapeutic strategies for liver cancer.
Topics: Animals; Carcinoma, Hepatocellular; Fibroblasts; Fibrosis; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Liver Neoplasms; Tumor Microenvironment
PubMed: 30959975
DOI: 10.3390/ijms20071723 -
The British Journal of Radiology Feb 2022Brenner tumors are rare ovarian neoplasms composed of ovarian transition cells surrounded by dense fibrous tissue. Most of them are small tumors (<2 cm), detected...
Brenner tumors are rare ovarian neoplasms composed of ovarian transition cells surrounded by dense fibrous tissue. Most of them are small tumors (<2 cm), detected incidentally in asymptomatic women. Its predominantly fibrous content results in relatively low signal on weighted images, establishing differential diagnosis with ovarian fibroma and thecoma. Their imaging features are very similar, the differentiation is based on secondary characteristics, such as signs or symptoms of estrogen excess and the presence of a second ovarian neoplasm, which has been reported in up to 30% of patients with Brenner tumor. Although originally thought to be universally benign, there have been scattered reports in the past decades of borderline and malignant forms of Brenner tumors.
Topics: Brenner Tumor; Cystadenofibroma; Diagnosis, Differential; Female; Fibroma; Humans; Leiomyoma; Magnetic Resonance Imaging; Ovarian Neoplasms; Rare Diseases; Thecoma; Tomography, X-Ray Computed; Ultrasonography
PubMed: 34928171
DOI: 10.1259/bjr.20210687 -
Physiological Reviews Jan 2019The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of... (Review)
Review
The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of cellular functions. The communication pathways mediated by TNFSF/TNFRSF are essential for numerous developmental, homeostatic, and stimulus-responsive processes in vivo. TNFSF/TNFRSF members regulate cellular differentiation, survival, and programmed death, but their most critical functions pertain to the immune system. Both innate and adaptive immune cells are controlled by TNFSF/TNFRSF members in a manner that is crucial for the coordination of various mechanisms driving either co-stimulation or co-inhibition of the immune response. Dysregulation of these same signaling pathways has been implicated in inflammatory and autoimmune diseases, highlighting the importance of their tight regulation. Investigation of the control of TNFSF/TNFRSF activities has led to the development of therapeutics with the potential to reduce chronic inflammation or promote anti-tumor immunity. The study of TNFSF/TNFRSF proteins has exploded over the last 30 yr, but there remains a need to better understand the fundamental mechanisms underlying the molecular pathways they mediate to design more effective anti-inflammatory and anti-cancer therapies.
Topics: Animals; Autoimmune Diseases; Humans; Immune System; Inflammation; Ligands; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factors
PubMed: 30354964
DOI: 10.1152/physrev.00045.2017 -
Cell Metabolism May 2020Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic...
Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.
Topics: Animals; Glutathione; Mice; Serine; T-Lymphocytes, Regulatory
PubMed: 32213345
DOI: 10.1016/j.cmet.2020.03.004 -
British Journal of Cancer Oct 2018Colorectal cancer (CRC) is both one of the most common and one of the most preventable cancers globally, with powerful but strongly missed potential for primary,... (Review)
Review
Colorectal cancer (CRC) is both one of the most common and one of the most preventable cancers globally, with powerful but strongly missed potential for primary, secondary and tertiary prevention. CRC incidence has traditionally been the highest in affluent Western countries, but it is now increasing rapidly with economic development in many other parts of the world. CRC shares several main risk factors, such as smoking, excessive alcohol consumption, physical inactivity and being overweight, with other common diseases; therefore, primary prevention efforts to reduce these risk factors are expected to have multiple beneficial effects that extend beyond CRC prevention, and should have high public health impact. A sizeable reduction in the incidence and mortality of CRC can also be achieved by offering effective screening tests, such as faecal immunochemical tests, flexible sigmoidoscopy and colonoscopy, in organised screening programmes which have been implemented in an increasing number of countries. Countries with early and high uptake rates of effective screening have exhibited major declines in CRC incidence and mortality, in contrast to most other countries. Finally, increasing evidence shows that the prognosis and quality of life of CRC patients can be substantially improved by tertiary prevention measures, such as the administration of low-dose aspirin and the promotion of physical activity.
Topics: Colorectal Neoplasms; Early Detection of Cancer; Epidemics; Healthy Lifestyle; Humans; Incidence; Primary Prevention; Prognosis; Risk Assessment; Secondary Prevention; Tertiary Prevention
PubMed: 30287914
DOI: 10.1038/s41416-018-0264-x -
Nature Medicine Jul 2019Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every...
Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.
Topics: Deep Learning; Gastrointestinal Neoplasms; Humans; Immunotherapy; Microsatellite Instability
PubMed: 31160815
DOI: 10.1038/s41591-019-0462-y -
The Journal of Clinical Investigation Aug 2016In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor...
In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Immunotherapy, Adoptive; Interleukin-13; Interleukin-13 Receptor alpha2 Subunit; Lymphocyte Activation; Mice; Mice, SCID; Neoplasm Recurrence, Local; Neoplasm Transplantation; Protein Binding; Protein Multimerization; Receptor, ErbB-2; Receptors, Antigen, T-Cell; T-Lymphocytes; Transgenes; Tumor Escape
PubMed: 27427982
DOI: 10.1172/JCI83416 -
Journal of Clinical Oncology : Official... May 2015The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has...
PURPOSE
The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma.
PATIENTS AND METHODS
We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) -positive sarcoma received escalating doses (1 × 10(4)/m(2) to 1 × 10(8)/m(2)) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells).
RESULTS
We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 10(5)/m(2)) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 10(6)/m(2) HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months).
CONCLUSION
This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence.
Topics: Adolescent; Adult; Bone Neoplasms; Child; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Neoplasm Metastasis; Neuroectodermal Tumors; Osteosarcoma; Positron-Emission Tomography; Receptor, ErbB-2; Receptors, Antigen, T-Cell; Recurrence; Sarcoma; Sarcoma, Ewing; T-Lymphocytes; Tomography, X-Ray Computed; Treatment Outcome; Young Adult
PubMed: 25800760
DOI: 10.1200/JCO.2014.58.0225 -
Frontiers in Oncology 2019Development of chimeric antigen receptor (CAR)-modified T cells for the treatment of T-lineage leukemia and lymphoma has encountered several unique challenges. The most... (Review)
Review
Development of chimeric antigen receptor (CAR)-modified T cells for the treatment of T-lineage leukemia and lymphoma has encountered several unique challenges. The most widely expressed tumor antigen targets for malignant T cells are often also expressed on non-malignant T cells. Transducing T cells with CARs targeted to these shared antigens can therefore promote over-activation or fratricide of CAR T cells, reducing their therapeutic potency. If fratricide is resolved, clinical CAR T cell activity may eliminate normal T-cell subsets and cause temporary immunosuppression. In this review, we summarize the preclinical development of CAR-based therapies for T-cell malignancies and discuss strategies to minimize toxicities associated with on-target fratricide and off-tumor activity.
PubMed: 30891427
DOI: 10.3389/fonc.2019.00126