Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy.

Osteoarthritis (OA) is a major cause of disability in the adult population. As a progressive degenerative joint disorder, OA is characterized by cartilage damage, changes in the subchondral bone, osteophyte formation, muscle weakness, and inflammation of the synovium tissue and tendon. Although OA has long been viewed as a primary disorder of articular cartilage, subchondral bone is attracting increasing attention. It is commonly reported to play a vital role in the pathogenesis of OA. Subchondral bone sclerosis, together with progressive cartilage degradation, is widely considered as a hallmark of OA. Despite the increase in bone volume fraction, subchondral bone is hypomineralized, due to abnormal bone remodeling. Some histopathological changes in the subchondral bone have also been detected, including microdamage, bone marrow edema-like lesions and bone cysts. This review summarizes basic features of the osteochondral junction, which comprises subchondral bone and articular cartilage. Importantly, we discuss risk factors influencing subchondral bone integrity. We also focus on the microarchitectural and histopathological changes of subchondral bone in OA, and provide an overview of their potential contribution to the progression of OA. A hypothetical model for the pathogenesis of OA is proposed.

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Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes

The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Patients with low-immunogenic tumors respond poorly to immune checkpoint blockade (ICB) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Conversely, patients responding to ICB can experience various side effects. We have thus engineered a therapeutic scaffold that, when formed in situ, allows the local release of gemcitabine (GEM) and an anti-PD-L1 blocking antibody (aPDL1) with distinct release kinetics. The scaffold consists of reactive oxygen species (ROS)-degradable hydrogel that releases therapeutics in a programmed manner within the tumor microenvironment (TME), which contains abundant ROS. We found that the aPDL1-GEM scaffold elicits an immunogenic tumor phenotype and promotes an immune-mediated tumor regression in the tumor-bearing mice, with prevention of tumor recurrence after primary resection.

In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy.

Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia–telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer.

L-selectin mediates the initial tethering and subsequent rolling of leucocytes along luminal walls of inflamed venules. TACE [TNFalpha (tumour necrosis factor alpha)-converting enzyme] is responsible for cleaving the membrane-proximal extracellular domain of L-selectin (also known as shedding), which reduces the efficiency of leucocyte recruitment to sites of inflammation. Many reports have highlighted roles for PKC (protein kinase C) and p38 MAPK (mitogen-activated protein kinase) in promoting L-selectin shedding with little insight into the mechanism involved. By using PMA and the phosphatase inhibitors cantharidin and calyculin A, we could selectively activate PKC or p38 MAPK respectively to promote TACE-dependent shedding of L-selectin. Interestingly, the intracellular mechanisms leading to the shedding event differed dramatically. For example, regulatory elements within the L-selectin cytoplasmic tail, such as ERM (ezrin/radixin/moesin)-binding and serine residues, were important for PKC- but not p38 MAPK-dependent shedding. Also, increased and sustained cell surface levels of TACE, and phosphorylation of its cytoplasmic tail (a hallmark of TACE activation), occurred in lymphocytes and monocytes following p38 MAPK activation. Finally, we showed that TNFalpha-induced shedding of L-selectin in monocytes was strikingly similar to cantharidin-induced shedding and suggest that this newly characterized mechanism could be physiologically relevant in inflammatory cells.

/pdf/the-cytoplasmic-domains-of-tnfa-converting-enzyme-tace-377ceuuhdr.pdf

The cytoplasmic domains of TNFα-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding

In Vitro and in Vivo Characterization of Molecular Interactions between Calmodulin, Ezrin/Radixin/Moesin, and L-selectin.

mammographic screening is widely used for the detection of breast cancers, but has its flaws. For example, false-positive findings can lead to unnecessary medical interventions and patient anxiety, whereas false-negative results delay diagnosis and potentially preclude cure. Now, collaboration between Google Health and physician scientists has resulted in an artificial intelligence (AI) approach with the potential to enhance the efficiency of breast cancer diagnosis. A deep learning-based AI system was trained using mammograms from ~76,000 women in the uK and >15,000 in the uSA, and was then retrospectively applied to uK and uS test sets comprising 25,856 and 3,097 women, respectively. The AI system resulted in absolute reductions of 1.2% and 2.7% in the rates of false-positive and false-negative detection of biopsy-confirmed breast cancers, respectively, in the uK test set and 5.7% and 9.4% in the uS dataset, relative to the judgement of the first or sole radiologists. “In our study, we addressed a common concern that machine learning results fail to generalise to new populations by re-training the algorithm using UK data only and then testing it on US data,” adds Google Health employee Shravya Shetty. “Despite a small drop in performance, the AI system continued to demonstrate a reduction in falsepositive and false-negative rates [3.5% and 8.1%, respectively].” When used to provide a rapid second opinion as part of the double-reading process used in the uK, the accuracy of the AI system was non-inferior to serial reading by two radiologists, and the simulated workload of the second reader was reduced by 88%. Thus, AI has the potential to alleviate pressures on services in the context of a worldwide shortage of radiologists. The survival benefits of mammographic screening, per se, continue to be debated and overdiagnosis is a key concern. Notably, the fundamental principles of AI in discerning patterns and associations that are often imperceptible to humans might, in the future, provide the capacity to distinguish clinically relevant and irrelevant cancers. “Further clinical studies are required to understand how software systems inspired by this research could improve patient care,” Shetty emphasizes, concluding that “the goal is to increase the accuracy, efficacy and efficiency of screening, as well as reduce patient wait times and stress.” David Killock B R E A S T C A N C E R

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AI outperforms radiologists in mammographic screening.

JCO.2014.58.3377 Breakthroughs in immunotherapy have led to new drug approvals, revolutionizing the management of melanoma. Now, on the basis of data from the phase III OPTiM trial, talimogene laherparepvec (T-VEC) looks set to be added to this armamentarium. T-VEC is an oncolytic viral therapy comprising attenuated herpes simplex virus type 1 that has been modified to mediate a two-pronged attack on tumours: selective lysis of cancer cells after local injection; and promotion of global antitumour immunity. The latter effect is achieved through integration of the granulocytemacrophage colony-stimulating factor (GM-CSF) gene into the viral genome, expression of which promotes local inflammation and antigen presentation. In OPTiM, 436 patients with advanced-stage accessible unresectable melanoma received either intralesional T-VEC or subcutaneous GM-CSF. No approved intralesional treatments and few systemic therapies were available for melanoma at the time of trial design. “Thus, we selected GM-CSF as it is part of the viral vector and some data suggested that it might have therapeutic activity in patients with stage III– IV disease,” says corresponding author Howard Kaufman. The durable response rate— objective responses occurring within 12 months of treatment initiation and lasting ≥6 months— was improved in the T-VEC group (16.3% versus 2.1%; P <0.001). As Kaufman explains, “this is a particularly challenging end point, as immunotherapy can result in delayed kinetics of response and maintaining durability is not typically required nor reported in clinical studies.” T-VEC also improved the overall response rate (26.4% versus 5.7%; P <0.001), and prolonged overall survival (median 23.3 months versus 18.9 months; P = 0.051). “Another very significant finding was that nearly 11% of patients who received T-VEC had an objective complete response, which has not been typically seen with other melanoma treatments,” Kaufman adds. Of note, although only accessible tumours were injected, responses required regression of all disease, including visceral sites. T-VEC treatment was well tolerated (most adverse effects were low-grade), which might be important when considering drug combinations. As T-VEC promotes a systemic antitumour immune response, combinations with immune-checkpoint inhibitors might be of particular interest. “Two trials in patients with melanoma are combining T-VEC with ipilimumab or pembrolizumab, and early results of the T-VEC and ipilimumab trial are promising, demonstrating a synergistic activity,” says Kaufman. He concludes, “a joint review panel have recommended that the FDA approve T-VEC for patients with unresectable and metastatic melanoma; thus, we widely anticipate final FDA approval later this year.”

Skin cancer: T-VEC oncolytic viral therapy shows promise in melanoma.

The clinical characteristics and prognosis of patients with grade II–III glioma and glioblastoma (grade IV glioma) are not accurately reflected by histological classifications. Two recent studies support the development of a new molecular classification. The Cancer Genome Atlas (TCGA) have identified three nonoverlapping disease subgroups based on unsupervised clustering of diverse omics data from 293 grade II–III gliomas. “These molecular subtypes did not correlate well with histological class, but correlated extremely well with biomarkers used clinically to characterize these tumours,” states Daniel Brat, who led the study. Two subgroups comprised gliomas with IDH (IDH1/2) mutations, but could be distinguished by the presence of either the t(1p;19q) chromosomal translocation (1p/19q codeletion), or TP53 mutations; the third disease subset was IDH wild-type. The TCGA study found TERT alterations in 64% and 90% of IDH-wild-type and IDH/t(1p;19q)mutant gliomas, respectively, but only 4% of IDH/TP53-mutated tumours. In the second study, these differences in TERT status, considered together with IDH and t(1p;19q) status, enabled Jeanette Eckel-Passow et al. to develop a classification that stratified 97.4% of 1,087 grade II–IV gliomas into five subtypes: tumours with IDH/ t(1p;19q)/TERT alterations; IDH/TERT mutations; IDH mutations only; TERT mutations only; or triple-negative gliomas. In both studies, the subgroups identified differed in terms of age at diagnosis and somatic alterations (see image), and the patterns observed were mostly consistent between the studies. Importantly, the glioma subtypes identified had prognostic significance. “The IDH-wild-type gliomas had genetic characteristics and an aggressive clinical behaviour similar to that of primary glioblastoma,” Brat explains. By contrast, IDHmutated, 1p/q19 codeleted gliomas had a predominantly oligodendroglial histology— typically associated with a good response to chemoradiotherapy— and the most favourable outcome. The studies also provided information on the process of glioma tumorigenesis, and linked molecular subgroups with specific germline mutations. “For example, while it is the rarest of the five molecular groups, IDH/TERTmutant glioma (without 1p/19q codeletion) is the only group that is associated with TP53 germline variants,” says Eckel-Passow. “Incorporating our molecular classification schema into a patient’s diagnosis will more-accurately predict their prognosis and help determine how they should be treated,” Eckel-Passow concludes. Brat adds, “enrolment and stratification of future clinical trials based on these molecular subsets should advance the development of effective therapies and uncover further predictive markers.”

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David Killock

Papers

The cytoplasmic domains of TNFα-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding

In Vitro and in Vivo Characterization of Molecular Interactions between Calmodulin, Ezrin/Radixin/Moesin, and L-selectin.

AI outperforms radiologists in mammographic screening.

Skin cancer: T-VEC oncolytic viral therapy shows promise in melanoma.

CNS cancer: molecular classification of glioma.