To characterize the role of B cells on human papilloma virus (HPV)-associated cancer patient outcomes and determine the effects of radiation and PD-1 blockade on B-cell populations.
Tumor ...RNA-sequencing data from over 800 patients with head and neck squamous cell carcinoma (HNSCC) and cervical cancer, including a prospective validation cohort, was analyzed to study the impact of B-cell gene expression on overall survival (OS). A novel murine model of HPV
HNSCC was used to study the effects of PD-1 blockade and radiotherapy on B-cell activation, differentiation, and clonality including analysis by single-cell RNA-sequencing and B-cell receptor (BCR)-sequencing. Human protein microarray was then used to quantify B-cell-mediated IgG and IgM antibodies to over 16,000 proteins in the serum of patients treated on a clinical trial with PD-1 blockade.
RNA-sequencing identified
and
as novel B-cell prognostic biomarkers for 3-year OS (HR, 0.545;
< 0.001). PD-1 blockade and radiotherapy enhance development of memory B cells, plasma cells, and antigen-specific B cells. BCR-sequencing found that radiotherapy enhances B-cell clonality, decreases CDR3 length, and induces B-cell somatic hypermutation. Single-cell RNA-sequencing identified dramatic increases in B-cell germinal center formation after PD-1 blockade and radiotherapy. Human proteome array revealed enhanced IgG and IgM antibody responses in patients who derived clinical benefit but not those with progressive disease after treatment with PD-1 blockade.
These findings establish a key role for B cells in patient outcomes and responses to PD-1 blockade in HPV-associated squamous cell carcinomas and demonstrate the need for additional diagnostics and therapeutics targeting B cells.
Non small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality world-wide and the majority of cases are diagnosed at late stages of disease. There is currently no cost-effective ...screening test for NSCLC, and the development of such a test is a public health imperative. Recent studies have suggested that chest computed tomography screening of patients at high risk of lung cancer can increase survival from disease, however, the cost effectiveness of such screening has not been established. In this Phase I/II biomarker study we examined the feasibility of using serum miRNA as biomarkers of NSCLC using RT-qPCR to examine the expression of 180 miRNAs in sera from 30 treatment naive NSCLC patients and 20 healthy controls. Receiver operating characteristic curves (ROC) and area under the curve were used to identify differentially expressed miRNA pairs that could distinguish NSCLC from healthy controls. Selected miRNA candidates were further validated in sera from an additional 55 NSCLC patients and 75 healthy controls. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs. A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100% in the training set. Upon further testing on additional 130 subjects (55 NSCLC and 75 healthy controls), this miRNA pair predicted NSCLC with a specificity of 84% (95% CI 0.73-0.91), sensitivity of 100% (95% CI; 0.93-1.0), NPV of 100%, and PPV of 82%. These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of NSCLC. Further testing in a Phase III biomarker study in is necessary for validation of these results.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of B cells in the tumor microenvironment and B-cell-mediated antitumor immune responses remains relatively understudied. Recent seminal studies have discovered that B cells and associated ...tertiary lymphoid structures correlate with responses to checkpoint blockade immunotherapy and are prognostic for overall survival of cancer patients. B-cell subsets have remarkable functional diversity and include professional antigen-presenting cells, regulatory cells, memory populations, and antibody-producing plasma cells. Importantly, secreted antibodies can independently activate innate immune responses and induce the cancer immunity cycle. Thus, B cells and B-cell-mediated antibody responses comprise the largely underappreciated second arm of the adaptive immune system and certainly deserve further attention in the field of oncology. Here, we review the known functions of B cells in the tumor microenvironment, the contribution of B cells to the antitumor activity of immunotherapies, and the role of B cells in the overall survival of cancer patients.
Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United ...States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC.
The expression of cannabinoid receptors
and
was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of
and
in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS).
In TCGA cohort, the expression of
and
was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of
/
expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure.
Cannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.
Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. Although human papillomavirus (HPV)-associated HNSCCs have better overall ...survival compared with HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however, multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016, the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum-based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immunomodulation in HNSCC pathogenesis, response to treatment, and disease control. However, although immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.
Objectives
Most transoral robotic surgery (TORS) literature for HPV‐positive oropharyngeal squamous cell carcinoma (HPV‐OPC) derives from high‐volume tertiary‐care centers. This study aims to ...describe long‐term recurrence and survival outcomes among Veterans Health Administration patients.
Materials and Methods
Using the US Veterans Affairs database, we identified patients with HPV‐OPC treated with TORS between January 2010 and December 2016. Patients were stratified in risk categories: low (0–1 metastatic nodes, negative margins), intermediate (close margins, 2–4 metastatic nodes, lymphovascular or perineural invasion, pT3‐pT4 tumor), or high (positive margins, extranodal extension (ENE), and/or ≥5 metastatic nodes). Primary outcomes included overall survival (OS), disease‐specific survival (DSS), and recurrence‐free survival (RFS).
Results
The cohort included 161 patients of which 29 (18%) were low‐risk, 45 (28%) intermediate‐risk, and 87 (54%) high‐risk. ENE was present in 41% of node‐positive cases and 24% had positive margins. Median follow‐up was 5.6 years (95% CI, 3.0–9.3). The 5‐year DSS for low, intermediate, and high‐risk groups were: 100%, 90.0% (95% CI, 75.4–96.1%), and 88.7% (95% CI, 78.3–94.2%). Pathologic features associated with poor DSS on univariable analysis included pT3‐T4 tumors (HR 3.81, 95% CI, 1.31–11; p = 0.01), ≥5 metastatic nodes (HR 3.41, 95% CI, 1.20–11; p = 0.02), and ENE (HR 3.53, 95% CI, 1.06–12; p = 0.04). Higher 5‐year cumulative incidences of recurrence were observed in more advanced tumors (pT3‐T4, 33% 95% CI, 14–54% versus pT1‐T2, 13% 95% CI, 8–19%; p = 0.01).
Conclusions
In this nationwide study, patients with HPV‐OPC treated with TORS followed by adjuvant therapy at Veterans Affairs Medical Centers demonstrated favorable survival outcomes comparable to those reported in high‐volume academic centers and clinical trials.
Level of Evidence
4 Laryngoscope, 134:207–214, 2024
Using the US Veterans Affairs database, we identified 161 patients with HPV‐positive oropharyngeal carcinoma treated with TORS of which 29 (18%) were low‐risk, 45 (28%) intermediate‐risk, and 87 (54%) high‐risk. TORS followed by adjuvant treatment revealed 5‐year DSS of 100%, 90%, and 89% for low, intermediate, and high‐risk patients. ENE, pT3/T4 tumor, and >5 pathologic lymph nodes were associated with poor DSS. Cumulative incidence of first recurrence was 17%, 18%, and 13% and of distant metastasis was 0%, 12%, and 8%.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates ...for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998-2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998-2002 and 2008-2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad ...dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human papillomavirus type 16 (HPV-16) is a major causative factor in oropharyngeal squamous cell carcinoma (OPSCC). The detection of primary OPSCC is often delayed owing to the challenging anatomy of ...the oropharynx.
To investigate the feasibility of HPV-16 DNA detection in pretreatment and posttreatment plasma and saliva and its potential role as a marker of prognosis.
This is a retrospective analysis of a prospectively collected cohort. Among a cohort of patients with oropharyngeal and unknown primary squamous cell carcinoma with known HPV-16 tumor status from the Johns Hopkins Medical Institutions and Greater Baltimore Medical Center (from 1999 through 2010), 93 patients were identified with a complete set of pretreatment and posttreatment plasma or saliva samples, of which 81 patients had HPV-16-positive tumors and 12 patients had HPV-16-negative tumors. Real-time quantitative polymerase chain reaction was used to detect HPV-16 E6 and E7 DNA in saliva and plasma samples.
Main outcomes included sensitivity, specificity, negative predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status, as well as the association of posttreatment HPV DNA status with clinical outcomes, including recurrence-free survival and overall survival.
The median follow-up time was 49 months (range, 0.9-181.0 months). The sensitivity, specificity, negative predictive value, and positive predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status were 76%, 100%, 42%, and 100%, respectively. The sensitivities of pretreatment saliva or plasma alone were 52.8% and 67.3%, respectively. In a multivariable analysis, positive posttreatment saliva HPV status was associated with higher risk of recurrence (hazard ratio HR, 10.7; 95% CI, 2.36-48.50) (P = .002). Overall survival was reduced among those with posttreatment HPV-positive status in saliva (HR, 25.9; 95% CI, 3.23-208.00) (P = .002) and those with HPV-positive status in either saliva or plasma but not among patients with HPV-positive status in plasma alone. The combined saliva and plasma posttreatment HPV-16 DNA status was 90.7% specific and 69.5% sensitive in predicting recurrence within 3 years.
Using a combination of pretreatment plasma and saliva can increase the sensitivity of pretreatment HPV-16 status as a tool for screening patients with HPV-16-positive OPSCC. In addition, analysis of HPV-16 DNA in saliva and plasma after primary treatment may allow for early detection of recurrence in patients with HPV-16-positive OPSCC.
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