Human papillomavirus (HPV)-positive (HPV
) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent ...(8th) edition of the UICC/AJCC staging system separates HPV
OPSCC from its HPV-negative (HPV
) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV
OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV
OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes.
APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells, and APOBEC signature mutations occur ...at high frequency in cervical cancers (CESC), over 99% of which are caused by human papillomavirus (HPV). We tested whether APOBEC-mediated mutagenesis is particularly important in HPV-associated tumors by comparing the exomes of HPV+ and HPV− head and neck squamous cell carcinomas (HNSCCs) sequenced by The Cancer Genome Atlas project. As expected, HPV− HNSCC displays a smoking-associated mutational signature, whereas our data suggest that reduced exposure to exogenous carcinogens in HPV+ HNSCC creates a selective pressure that favors emergence of tumors with APOBEC-mediated driver mutations. Finally, we provide evidence that APOBEC activity is responsible for the generation of helical domain hot spot mutations in the PIK3CA gene across multiple cancers. Our findings implicate APOBEC activity as a key driver of PIK3CA mutagenesis and HPV-induced transformation.
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•APOBEC-mediated mutagenesis is increased in the HPV+ subset of head and neck cancer•APOBEC enzymes likely generate many of the driver mutations in HPV-associated cancers•APOBECs are implicated in generating the oncogenic E542K and E545K PIK3CA mutations
The APOBEC family of cytidine deaminases, which combat viral infection by hyperediting viral DNA, has recently been implicated in producing somatic mutations in human tumors. By analyzing mutation data from The Cancer Genome Atlas project, Henderson et al. provide evidence that this process plays a key role in tumor development by generating oncogenic hot spot mutations in the PIK3CA gene. This mechanism appears particularly prominent in tumors caused by the human papillomavirus, in which APOBEC activity accounts for a high fraction of the total mutational burden.
The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, ...we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: 'immune hot' and 'immune cold', which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy.
•APOBEC3 editing of HPV genomes plays a role in viral clearance but deamination of the host genome can drivecarcinogenesis.•Induction of DNA damage responses by HPV establishes a feed-forward loop, ...or ‘perfect storm’ for APOBEC3 activity.•APOBEC3 induction may allow cells to survive the DNA damage associated with viral genome replication.
Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting ...functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38 and found that CAFs broadly suppressed response by specifically excluding CD8
T cells from tumors (not CD4
T cells or macrophages); CD8
T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8
T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8
T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition GKT137831 (Setanaxib) of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8
T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8
T-cell exclusion. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg.
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The interaction between human papillomaviruses (HPV) and the apolipoprotein-B mRNA-editing catalytic polypeptide-like (APOBEC)3 (A3) genes has garnered increasing attention in recent years, with ...considerable efforts focused on understanding their apparent roles in both viral editing and in HPV-driven carcinogenesis. Here, we review these developments and highlight several outstanding questions in the field. We consider whether editing of the virus and mutagenesis of the host are linked or whether both are essentially separate events, coincidentally mediated by a common or distinct A3 enzymes. We discuss the viral mechanisms and cellular signalling pathways implicated in A3 induction in virally infected cells and examine which of the A3 enzymes might play the major role in HPV-associated carcinogenesis and in the development of therapeutic resistance. We consider the parallels between A3 induction in HPV-infected cells and what might be causing aberrant A3 activity in HPV-independent cancers such as those arising in the bladder, lung and breast. Finally, we discuss the implications of ongoing A3 activity in tumours under treatment and the therapeutic opportunities that this may present.
Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that ...activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.
Purpose In squamous cell carcinomas of the head and neck (HNSCC), the increasing incidence of oropharyngeal squamous cell carcinomas (OPSCCs) is attributable to human papillomavirus (HPV) infection. ...Despite commonly presenting at late stage, HPV-driven OPSCCs are associated with improved prognosis compared with HPV-negative disease. HPV DNA is also detectable in nonoropharyngeal (non-OPSCC), but its pathogenic role and clinical significance are unclear. The objectives of this study were to determine whether HPV plays a causal role in non-OPSCC and to investigate whether HPV confers a survival benefit in these tumors. Methods Meta-analysis was used to build a cross-tissue gene-expression signature for HPV-driven cancer. Classifiers trained by machine-learning approaches were used to predict the HPV status of 520 HNSCCs profiled by The Cancer Genome Atlas project. DNA methylation data were similarly used to classify 464 HNSCCs and these analyses were integrated with genomic, histopathology, and survival data to permit a comprehensive comparison of HPV transcript-positive OPSCC and non-OPSCC. Results HPV-driven tumors accounted for 4.1% of non-OPSCCs. Regardless of anatomic site, HPV+ HNSCCs shared highly similar gene expression and DNA methylation profiles; nonkeratinizing, basaloid histopathological features; and lack of TP53 or CDKN2A alterations. Improved overall survival, however, was largely restricted to HPV-driven OPSCCs, which were associated with increased levels of tumor-infiltrating lymphocytes compared with HPV-driven non-OPSCCs. Conclusion Our analysis identified a causal role for HPV in transcript-positive non-OPSCCs throughout the head and neck. Notably, however, HPV-driven non-OPSCCs display a distinct immune microenvironment and clinical behavior compared with HPV-driven OPSCCs.
Cancer drug development is hindered by high clinical attrition rates, which are blamed on weak predictive power by preclinical models and limited replicability of preclinical findings. However, the ...technically feasible level of replicability remains unknown. To fill this gap, we conducted an analysis of data from the NCI60 cancer cell line screen (2.8 million compound/cell line experiments), which is to our knowledge the largest depository of experiments that have been repeatedly performed over decades. The findings revealed profound intra-laboratory data variability, although all experiments were executed following highly standardised protocols that avoid all known confounders of data quality. All compound/ cell line combinations with > 100 independent biological replicates displayed maximum GI50 (50% growth inhibition) fold changes (highest/ lowest GI50) > 5% and 70.5% displayed maximum fold changes > 1000. The highest maximum fold change was 3.16 × 1010 (lowest GI50: 7.93 ×10-10 µM, highest GI50: 25.0 µM). FDA-approved drugs and experimental agents displayed similar variation. Variability remained high after outlier removal, when only considering experiments that tested drugs at the same concentration range, and when only considering NCI60-provided quality-controlled data. In conclusion, high variability is an intrinsic feature of anti-cancer drug testing, even among standardised experiments in a world-leading research environment. Awareness of this inherent variability will support realistic data interpretation and inspire research to improve data robustness. Further research will have to show whether the inclusion of a wider variety of model systems, such as animal and/ or patient-derived models, may improve data robustness.
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