Immunoregulatory Potential of Exosomes Derived from Cancer Stem Cells.

Head and neck squamous cell carcinomas (HNSCCs) are malignancies that originate in the mucosal lining of the upper aerodigestive tract. Despite advances in therapeutic interventions, survival rates among HNSCC patients have remained static for years. Cancer stem cells (CSCs) are tumor-initiating cells that are highly resistant to treatment, and are hypothesized to contribute to a significant fraction of tumor recurrences. Consequently, further investigations of how CSCs mediate recurrence may provide insights into novel druggable targets. A key element of recurrence involves the tumor's ability to evade immunosurveillance. Recent published reports suggest that CSCs possess immunosuppressive properties, however, the underlying mechanism have yet to be fully elucidated. To date, most groups have focused on the role of CSC-derived secretory proteins, such as cytokines and growth factors. Here, we review the established immunoregulatory role of exosomes derived from mixed tumor cell populations, and propose further study of CSC-derived exosomes may be warranted. Such studies may yield novel insights into new druggable targets, or lay the foundation for future exosome-based diagnostics

The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial

Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8+T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1+macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies

Controversies in free tissue transfer for head and neck cancer: A review of the literature

Microvascular free tissue transfer provides superior functional outcomes when reconstructing head and neck cancer defects. Careful patient selection and surgical planning is necessary to ensure success, as many preoperative, intraoperative, and postoperative patient and technical factors may affect outcome. To provide a concise, yet thorough, review of the current literature regarding free flap patient selection and management for the patient with head and neck. PubMed and Cochrane databases were queried for publications pertaining to free tissue transfer management and outcomes. Malnutrition and tobacco use are modifiable patient factors that negatively impact surgical outcomes. The use of postoperative antiplatelet medications and perioperative antibiotics for greater than 24 hours have not been shown to improve outcomes, although the use of clindamycin alone has been shown to have a higher risk of flap failure. Liberal blood transfusion should be avoided due to higher risk of wound infection and medical complications. There is a wide range of beliefs regarding proper management of patients undergoing free tissue transfer. While there is some data to support these practices, much of the data is conflicting and common practices are often continued out of habit or dogma. Free flap reconstruction remains a highly successful surgery overall despite as many different approaches to patient care as there are free flap surgeons. Close patient monitoring remains a cornerstone of surgical success

The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial

Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8+T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1+macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies

Polyamine Metabolites as Biomarkers in Head and Neck Cancer Biofluids.

Background: Novel, non-invasive diagnostic biomarkers that facilitate early intervention in head and neck cancer are urgently needed. Polyamine metabolites have been observed to be elevated in numerous cancer types and correlated with poor prognosis. The aim of this study was to assess the concentration of polyamines in the saliva and urine from head and neck cancer (HNC) patients, compared to healthy controls. Methods: Targeted metabolomic analysis was performed on saliva and urine from 39 HNC patient samples and compared to 89 healthy controls using a quantitative, targeted liquid chromatography mass spectrometry approach. Results: The metabolites N1-acetylspermine (ASP), N8-acetylspermidine (ASD) and N1,N12-diacetylspermine (DAS) were detected at significantly different concentrations in the urine of HNC patients as compared to healthy controls. Only ASP was detected at elevated levels in HNC saliva as compared to healthy controls. Conclusion: These data suggest that assessment of polyamine-based metabolite biomarkers within the saliva and urine warrants further investigation as a potential diagnostic in HNC patients