Immune modulation of CD4+CD25+ regulatory T cells by zoledronic acid.

BACKGROUND: CD4+CD25+ regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. Manipulation of Treg cells represents a new strategy for cancer treatment. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts to inhibit osteoclastogenesis. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells. However, the interaction between ZA and Treg cells remained unclear. This study investigated the immune modulation of Treg cells by ZA. METHODS: Flow cytometry was used to analyze the phenotypic and immunosuppressive characteristics of Treg cells treated with ZA. Chemotactic migration was evaluated using transwell assays. Quantitative real-time PCR (qRT-PCR) was used to investigate the effect of ZA on the expression of suppressive molecules by Treg cells. RESULTS: Proliferation of isolated Treg cells in culture was inhibited by ZA, although ZA did not induce apoptosis. qRT-PCR and flow cytometry showed that ZA significantly downregulated the expression of CCR4, CTLA4, PD-1 and RANKL on Treg cells. Chemotactic migration and immunosuppressive functions were also significantly attenuated in Treg cells pretreated with ZA, and these effects were dose-dependent. Co-culture with Treg cells significantly increased the migration rate of breast cancer cells, while pretreatment of Treg cells with ZA attenuated this effect. CONCLUSIONS: Our findings demonstrated that ZA acted as an immune modulator by significantly inhibiting the expansion, migration, immunosuppressive function and pro-metastatic ability of Treg cells. Immunomodulation of Treg cells by ZA represents a new strategy for cancer therapy.

Human papillomavirus infection on initiating synchronous esophageal neoplasia in patients with head and neck cancer.

OBJECTIVES/HYPOTHESIS: Human papillomavirus (HPV) is a risk factor for head and neck squamous cell carcinoma (HNSCC) as well as esophageal squamous cell carcinoma (ESCC). We aimed to investigate whether HPV infection underlies the field cancerization phenomenon over upper aerodigestive tract to develop synchronous multiple cancers. STUDY DESIGN: A case control study. METHODS: The presence and subtype of HPV-DNA sequence in cancers were examined by polymerase chain reaction and sequencing in a prospective cohort with 100 HNSCCs, 50 of which had synchronous ESCCs. The clinicopathologic characteristics were further analyzed according to the presence of HPV. RESULTS: Twelve patients were HPV-positive, of which 11 were positive for HPV-16. The prevalence of HPV infection were not different between the synchronous and HNSCC alone groups (P = 0.357). Testing for HPV in paired HNSCC and ESCC tissues from the same patient revealed that none were concomitantly HPV-positive. Multivariate logistic regression showed drinking alcohol (odds ratio [OR], 18.75; P = 0.030), alcohol flushing (OR, 2.53; P = 0.041), and body mass index (OR, 0.77; P = 0.001) but not HPV infection were independent risk factors for synchronous phenotype. The patients with synchronous ESCCs had significantly poorer survival than those with HNSCC alone (5-year overall survival: 30% vs. 70%; log-rank P < 0.001). However, patients with HPV-positive HNSCC tend to have favorable outcome than those with HPV-negative HNSCC. CONCLUSIONS: HPV infection plays little role in field cancerization phenomenon to initiate synchronous SCC. The synchronous HNSCC and ESCC from the same patients had no clonal relationship. Routine endoscopic examination of the esophagus should be recommended for patients with risk factors identified. LEVELS OF EVIDENCE: NA. Laryngoscope, 126:1097-1102, 2016.

The impact of human papillomavirus infection on the survival and treatment response of patients with esophageal cancers.

OBJECTIVE: This study aimed to investigate the impact of human papillomavirus (HPV) infection on the prognosis and treatment response of esophageal squamous cell carcinoma (ESCC). METHODS: We examined the presence and subtypes of HPV in the tumors by polymerase chain reaction and sequencing in 150 ESCC patients. Their clinicopathological characteristics, treatment response and survival were further analyzed according to the presence of HPV infection. RESULTS: Of 150 ESCC tumor samples, 27 (18.0%) were HPV-positive, of which 22 (81.5%) had HPV-16 infection. The risk of developing multifocal ESCC was not significantly different in the HPV-positive and HPV-negative groups (29.6% vs 28.5%, P = 0.90). In subgroup analysis, patients with HPV-16-positive advanced ESCC had a significantly better survival than those with HPV-negative ESCC (3-year survival: 55% vs 21%, log-rank P = 0.03). Cox proportional hazards model showed that the presence of HPV-16 was associated with a significant reduction in the mortality rate (hazard ratio 0.41, 95% CI 0.18-0.96). Patients with HPV-16 infection had better response to chemoradiotherapy (CRT) than those without HPV-16 infection (P = 0.026). CONCLUSIONS: In patients with advanced ESCC, HPV-16-positive patients had a significantly favorable survival, especially those who received CRT. Larger scale studies are needed to determine the causal relationship.

The benefit of pretreatment esophageal screening with image-enhanced endoscopy on the survival of patients with hypopharyngeal cancer.

BACKGROUND: Synchronous esophageal cancers can suppress the survival of patients with hypopharyngeal cancers. Esophageal screening with the image-enhanced endoscopy may identify more synchronous cancers while there is no evidence to support its benefit on survival. METHODS: A total of 281 and 320 patients were diagnosed with hypopharyngeal cancer before and after the policy of routine esophageal screening. Primary outcome measures were overall survival. RESULTS: Among those who received screening, 49 patients (49/180, 27.2%) had synchronous esophageal cancers; treatment planning was changed in 42 (23.3%). Before and after the policy, percentages of stage I-II synchronous cancers were 20% (3/15) and 53.1% (26/49), respectively. Adjunctive therapies for synchronous cancers have led to a better survival after the policy than before (P = 0.002). The Cox regression model quantified a survival benefit of 29% (95% CI: 11-43%) when adjusting for TNM stage of hypopharyngeal cancer. In post-policy period, the survival was better for those who chose screening than those who did not (HR: 0.57, 95% CI: 0.41-0.79). Among those without screening, there was no difference between the pre- and post-policy periods (HR: 0.96, 95% CI: 0.74-1.26). CONCLUSIONS: Patients with hypopharyngeal cancers may benefit from the esophageal screening with image-enhanced endoscopy through the better detection of early-stage synchronous cancers.