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Validation and promise of a TCR mimic antibody for cancer immunotherapy of hepatocellular carcinoma
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Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation
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Oncogenic Ras and ΔNp63α cooperate to recruit immunosuppressive polymorphonuclear myeloid-derived suppressor cells in a mouse model of squamous cancer pathogenesis
Introduction Amplification of human chromosome 3q26-29, which encodes oncoprotein ΔNp63 among other isoforms of the p63 family, is a feature common to squamous cell carcinomas (SCCs) of multiple tissue origins. Along with overexpression of ΔNp63, activation of the protooncogene, RAS , whether by overexpression or oncogenic mutation, is frequently observed in many cancers. In this study, analysis of transcriptome data from The Cancer Genome Atlas (TCGA) demonstrated that expression of TP63 mRNA , particularly ΔNp63 isoforms, and HRAS are significantly elevated in advanced squamous cell carcinomas of the head and neck (HNSCCs), suggesting pathological significance. However, how co-overexpressed ΔNp63 and HRAS affect the immunosuppressive tumor microenvironment (TME) is incompletely understood. Methods Here, we established and characterized an immune competent mouse model using primary keratinocytes with retroviral-mediated overexpression of ΔNp63α and constitutively activated HRAS (v-ras Ha G12R) to evaluate the role of these oncogenes in the immune TME. Results In this model, orthotopic grafting of wildtype syngeneic keratinocytes expressing both v-ras Ha and elevated levels of ΔNp63α consistently yield carcinomas in syngeneic hosts, while cells expressing v-ras Ha alone yield predominantly papillomas. We found that polymorphonuclear (PMN) myeloid cells, experimentally validated to be immunosuppressive and thus representing myeloid-derived suppressor cells (PMN-MDSCs), were significantly recruited into the TME of carcinomas arising early following orthotopic grafting of ΔNp63α/v-ras Ha -expressing keratinocytes. ΔNp63α/v-ras Ha -driven carcinomas expressed higher levels of chemokines implicated in recruitment of MDSCs compared to v-ras Ha -initiated tumors, providing a heretofore undescribed link between ΔNp63α/HRAS-driven carcinomas and the development of an immunosuppressive TME. Conclusion These results support the utilization of a genetic carcinogenesis model harboring specific genomic drivers of malignancy to study mechanisms underlying the development of local immunosuppression.
Antineoplastic activity of Salmonella Typhimurium outer membrane nanovesicles
Highlights: • ST-OMVs is a promising antitumor monotherapy or as an adjuvant to chemotherapies. • ST-OMVs downregulated Ki-67 and upregulated CD49b immune-expression. • ST-OMVs downregulated angiogenesis by inhibiting VEGF gene expression. • ST-OMVs increased tumor cells apoptosis and autophagy (increased caspase-3and Beclin1). Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.
KRT18 as a Novel Biomarker of Urothelial Papilloma while Evaluating Low-Grade Papillary Urothelial Neoplasms: Bi-Center Analysis
Introduction: Although urothelial papilloma (UP) is an indolent papillary neoplasm that can mimic the morphology of low-grade papillary urothelial carcinoma (PUC), there is no immunomarker to differentiate reliably these two entities. In addition, the molecular characteristics of UP are not fully understood. Methods: We conducted an in-depth proteomic analysis of papillary urothelial lesions (n = 31), including UP and PUC along with normal urothelium. Protein markers distinguishing UP and PUC were selected with machine learning analysis, followed by internal and external validation using immunohistochemistry. Results: In the proteomic analysis, UP and PUC showed overlapping proteomic profiles. Here, we identified EHD4 and KRT18 as candidate diagnostic biomarkers of UP. Through immunohistochemical validation in two independent cohorts (n = 120), KRT18 was suggested as a novel UP diagnostic marker, able to differentiate UP from low-grade PUC. We also found that 3.5% of patients with UP developed urothelial carcinoma in subsequent resections, supporting the malignant potential of UP. KRT18 downregulation was significantly associated with UPs subsequently progressing to urothelial carcinoma, following their initial diagnosis. Conclusion: This is the first study that successfully revealed UPs comprehensive proteomic landscape, while it also identified KRT18 as a potential diagnostic biomarker of UP.
Risk and incidence of head and neck cancers in veterans living with HIV and matched HIV‐negative veterans
Background Persons living with HIV/AIDS have a higher incidence of virus‐related and tobacco/alcohol‐related cancers. This study is the first to estimate the effect of HIV versus HIV‐negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. Methods The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV‐negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age‐standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. Results Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV‐negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV‐positive ( N = 30 [81.1%]) than the HIV‐negative veterans with OPSCC ( N = 50 [67.6%]), although this difference was not significant ( p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. Conclusions The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV‐positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.
Human adenylate kinase 6 regulates WNK1 (with no lysine kinase-1) phosphorylation states and affects ion homeostasis in NT2 cells
Highlights: • Depletion of AK6 inhibits cell proliferation and promotes apoptosis in NT2 cells. • AK6 interacts with N terminal of WNK1 and regulates its phosphorylation states. • AK6 mediates Akt/WNK1 signaling pathway and regulates ion homeostasis in NT2 cells. • Chloride channel CLC-3 is responsible for ion transport in NT2 cells. Adenylate kinase 6 (AK6), a nucleus localized phosphotransferase in mammalians, shows ubiquitously expression and broad substrate activity in different tissues and cell types. Although the function of AK6 has been extensively studied in different cancer cell lines, its role in mammalian germline is still unknown. Here we showed that knockdown of AK6 inhibits cell proliferation and promotes cell apoptosis in human testicular carcinoma (NT2 cells). Co-immunoprecipitation experiment and in vitro pull down assay identified WNK1 (with no lysine kinase-1) as one of the AK6 interacting proteins in NT2 cells. Moreover, we found that AK6 regulates the phosphorylation states of WNK1 (Thr60) and affects phosphorylation level of Akt (Ser473) upon hypotonic condition, probably affecting chloride channel and regulating ion transport and homeostasis in NT2 cells and consequently contributing to the decreased cell proliferation rate. In conclusion, AK6 regulates WNK1 phosphorylation states and affects ion homeostasis in NT2 cells. These findings provide new insights into the function of AK6 and WNK1 in human testicular carcinoma. This work also provides foundation for further mechanism study of AK6 in spermatogenesis.
Subnetwork representation learning for discovering network biomarkers in predicting lymph node metastasis in early oral cancer
Cervical lymph node metastasis is the leading cause of poor prognosis in oral tongue squamous cell carcinoma and also occurs in the early stages. The current clinical diagnosis depends on a physical examination that is not enough to determine whether micrometastasis remains. The transcriptome profiling technique has shown great potential for predicting micrometastasis by capturing the dynamic activation state of genes. However, there are several technical challenges in using transcriptome data to model patient conditions: (1) An Insufficient number of samples compared to the number of genes, (2) Complex dependence between genes that govern the cancer phenotype, and (3) Heterogeneity between patients between cohorts that differ geographically and racially. We developed a computational framework to learn the subnetwork representation of the transcriptome to discover network biomarkers and determine the potential of metastasis in early oral tongue squamous cell carcinoma. Our method achieved high accuracy in predicting the potential of metastasis in two geographically and racially different groups of patients. The robustness of the model and the reproducibility of the discovered network biomarkers show great potential as a tool to diagnose lymph node metastasis in early oral cancer.
RhoA and vigilin are candidates for immunohistochemical markers for epithelioid malignant mesothelioma
Diagnostic markers of malignant mesothelioma (MM) have been extensively investigated. Immunohistochemistry (IHC) markers, such as calretinin, have been used for pathologic diagnosis. However, more diagnostic markers are required to improve the specificity and sensitivity of pathologic diagnosis. This study proposed two proteins as diagnostic markers for epithelioid MM. One is RhoA, an MM mutation-susceptible locus-derived protein, and another is vigilin, a lung small cell carcinoma marker. IHC was performed using 93 MM (epithelioid, 71 cases; sarcomatoid, 13 cases; and biphasic, 9 cases), 64 lung adenocarcinoma (LAC), 60 lung squamous cell carcinoma (LSC), and 14 normal mesothelial (NM) tissues. The majority of epithelioid MM cases were positive for both RhoA and vigilin, whereas both IHCs showed lower stainability in biphasic and sarcomatoid MM. Besides, both IHCs showed significantly higher stainability for RhoA and vigilin in epithelioid MM than in LAC and LSC (p < 0.05). Chi-square tests showed that both RhoA and vigilin IHC positive rate in epithelioid MM was not significantly different from that of calretinin (p > 0.05). In the differential diagnosis of MM from lung cancer, the accuracy and specificity of RhoA, vigilin, and calretinin staining were almost equivalent. Further, H-score test showed that there was no significant difference between RhoA versus calretinin and vigilin versus calretinin in IHC positivity in epithelioid MM (p > 0.05). In conclusion, RhoA and vigilin may be candidates for immunohistochemical markers for epithelioid MM.
Assessment of Clonal Expansion Using CarcSeq Measurement of Lung Cancer Driver Mutations and Correlation With Mouse Strain- and Sex-Related Incidence of Spontaneous Lung Neoplasia
Quantification of variation in levels of spontaneously occurring cancer driver mutations (CDMs) was developed to assess clonal expansion and predict future risk of neoplasm development. Specifically, an error-corrected next-generation sequencing method, CarcSeq, and a mouse CarcSeq panel (analogous to human and rat panels) were developed and used to quantify low-frequency mutations in a panel of amplicons enriched in hotspot CDMs. Mutations in a subset of panel amplicons, Braf, Egfr, Kras, Stk11, and Tp53, were related to incidence of lung neoplasms at 2 years. This was achieved by correlating median absolute deviation (MAD) from the overall median mutant fraction (MF) measured in the lung DNA of 16-week-old male and female, B6C3F1 and CD-1 mice (10 mice/sex/strain) with percentages of spontaneous alveolar/bronchioloalveolar adenomas and carcinomas reported in bioassay control groups. A total of 1586 mouse lung mutants with MFs > x 10-4 were recovered. The ratio of nonsynonymous to synonymous mutations was used to assess the proportion of recovered mutations conferring a positive selective advantage. The greatest ratio was observed in what is considered the most lung tumor-sensitive model examined, male B6C3F1 mice. Of the recurrent, nonsynonymous mouse mutations recovered, 55.5% have been reported in human tumors, with many located in or around the mouse equivalent of human cancer hotspot codons. MAD for the same subset of amplicons measured in normal human lung DNA samples showed a correlation of moderate strength and borderline significance with age (a cancer risk factor), as well as age-related cumulative lung cancer risk, suggesting MAD may inform species extrapolation.
Mechanistic Insights into the Successful Development of Combination Therapy of Enfortumab Vedotin and Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer
Antibody–drug conjugates (ADCs) consist of an antibody backbone that recognizes and binds to a target antigen expressed on tumor cells and a small molecule chemotherapy payload that is conjugated to the antibody via a linker. ADCs are one of the most promising therapeutic modalities for the treatment of various cancers. However, many patients have developed resistance to this form of therapy. Extensive efforts have been dedicated to identifying an effective combination of ADCs with other types of anticancer therapies to potentially overcome this resistance. A recent clinical study demonstrated that a combination of the ADC enfortumab vedotin (EV) with the immune checkpoint inhibitor (ICI) pembrolizumab can achieve remarkable clinical efficacy as the first-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC)—leading to the first approval of a combination therapy of an ADC with an ICI for the treatment of cancer patients. In this review, we highlight knowledge and understanding gained from the successful development of EV and the combination therapy of EV with ICI for the treatment of la/mUC. Using urothelial carcinoma as an example, we will focus on dissecting the underlying mechanisms necessary for the development of this type of combination therapy for a variety of cancers.
Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors
Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal. Herein, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the transcriptional corepressor component protein NCoR. These pockets were screened using an ensemble docking approach combined with consensus scoring to identify compounds with a different binding mechanism than the currently known HDAC modulators. Binding was compared in experimental assays between HDAC4 and HDAC3, which belong to a different family of HDACs. HDAC4 was significantly inhibited by compound 88402 but not HDAC3. Two other compounds (67436 and 134199) had IC50 values in the low micromolar range for both HDACs, which is comparable to the known inhibitor of HDAC4, SAHA (Vorinostat). However, both of these compounds were significantly weaker inhibitors of HDAC3 than SAHA and thus more selective, albeit to a limited extent. Five compounds exhibited activity on human breast carcinoma and/or urothelial carcinoma cell lines. The present result suggests potential mechanistic and chemical approaches for developing selective HDAC4 modulators.
Simultaneous Reduction of Volume and Dose in Clinical Target Volume for Nasopharyngeal Cancer Patients
To compare the treatment outcome and severe late adverse effects (AEs) between conventional volume and dose (CVD) and simultaneously reduced volume and dose (SRVD) of clinical target volume treatments in patients with nasopharyngeal carcinoma.
Prospective Phase 2 Study of Radiation Therapy Dose and Volume De-escalation for Elective Neck Treatment of Oropharyngeal and Laryngeal Cancer
The required elective nodal dose and volumes for head and neck intensity modulated radiation therapy have largely been extrapolated from conventional radiation therapy fields. In this prospective, dual-center, phase 2 study, we investigated the efficacy and tolerability of reduced elective nodal volume and dose in oropharyngeal and laryngeal squamous cell carcinoma.
Costs of Definitive Chemoradiation, Surgery, and Adjuvant Radiation Versus De-Escalated Adjuvant Radiation per MC1273 in HPV+ Cancer of the Oropharynx
De-escalated treatment for human papillomavirus (HPV)+ oropharynx squamous cell carcinoma (OPSCC) has shown promising initial results. Health-care policy is increasingly focusing on high-value care. This analysis compares the cost of care for HPV+ OPSCC treated with definitive chemoradiation (CRT), surgery and adjuvant radiation (RT), and surgery and de-escalated CRT on MC1273.