TLR9 Mediated Tumor-Stroma Interactions in Human Papilloma Virus (HPV)-Positive Head and Neck Squamous Cell Carcinoma Up-Regulate PD-L1 and PD-L2.

Background: The co-inhibitory receptor PD-1 is expressed in many tumors including head and neck squamous cell carcinoma (HNSCC) and is an important immunotherapy target. However, the role of PD-1 ligands, PD-L1, and particularly PD-L2, in the tumor-stromal cell interactions that cause a tumor-permissive environment in HNSCC is not completely understood and is the focus of our study. Methods: Expression of PD-L1 and PD-L2 was analyzed by immunohistochemistry in situ in HNSCC tumor tissue. Co-cultures were established between stromal cells (fibroblasts and macrophages) and human papilloma virus (HPV)-positive and HPV-negative HNSCC cell lines (HNSCCs) and PD-1 ligands expression was analyzed using flow cytometry. Results: PD-L1 and PD-L2 were expressed both in tumor cells and stroma in HNSCC tissue in situ. In vitro, basal expression of PD-L1 and PD-L2 was low in HNSCCs and high on fibroblasts and macrophages. Interestingly, HPV-positive but not HPV-negative HNSCCs increased the expression of both PD-1 ligands on fibroblasts upon co-culture. This effect was not observed with macrophages. Conversely, both fibroblasts and macrophages increased PD-1 ligands on HPV-positive HNSCCs, whilst this was not observed in HPV-negative HNSCCs. Crucially, we demonstrate that up-regulation of PD-L1 and PD-L2 on fibroblasts by HPV-positive HNSCCs is mediated via TLR9. Conclusions: This work demonstrates in an in vitro model that HPV-positive HNSCCs regulate PD-L1/2 expression on fibroblasts via TLR9. This may open novel avenues to modulate immune checkpoint regulator PD-1 and its ligands by targeting TLR9.

Metastatic breast cancer presenting as a primary hindgut neuroendocrine tumour.

The examination of limited, potentially non-representative fragments of tumour tissue from a core biopsy can be misleading and misdirect subsequent treatment, especially in cases where a primary tumour has not been identified. This case report is of a 65-year-old woman presenting with a destructive sacral mass, diagnosed on radiological imaging and core biopsy as a hindgut neuroendocrine tumour, which on histopathological review of the subsequently resected tumour was found instead to represent a metastasis from an occult hormone-positive breast cancer with neuroendocrine features.

Ectopic thymus presenting as a subglottic mass: diagnostic and management dilemmas.

The commonest subglottic mass in infants is a congenital haemangioma, which is usually managed conservatively without a histological diagnosis. Ectopic cervical thymus is rare and usually presents as a cervical mass, with only one case of subglottic ectopic thymus reported to date. Due to its rarity, the diagnosis in most cases relies on surgical excision and histological examination. However, histological diagnosis may not always be easily reached, as is demonstrated in this case report. In this article, an infant with congenital stridor secondary to a subglottic mass is described and the clinical and diagnostic difficulties in its management are discussed.