CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells.

BACKGROUND: While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive. METHODS: Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances TH9 cell antitumor activity against mouse melanoma upon adoptive transfer. RESULTS: We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of TH1 and TH9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of TH1 cell differentiation. However, STING activation favors TH9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on TH1 and TH9-derived cytokines, and STING activation enhances the antitumor activity of TH9 cells upon adoptive transfer. CONCLUSION: Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.

A prospective pilot study on the effects of endoscopic sinus surgery on upper and lower airway performance.

OBJECTIVE: The relationship between chronic rhinosinusitis, asthma and allergic rhinitis is well known, but only recently has the scientific community started to evaluate these as different manifestations of a common pathogenic phenomenon, considering them as a unified airway disease. METHODS: Twenty-two patients with chronic rhinosinusitis treated with endoscopic sinus surgery (ESS) were included in the study. Sino-nasal assessment questionnaire (SNAQ) investigating subjective evaluation of sino-nasal state was administered to patients, while objective evaluations included nasal endoscopy, sinonasal CT, skin prick tests, nasal cytology, spirometry, bronchodilator responsiveness testing and sputum eosinophil count. All tests were performed before surgery. Two months after surgery, SNAQ questionnaire, nasal endoscopy, spirometry and bronchodilator responsiveness testing were repeated. RESULTS: All patients had significant improvement of subjective status: mean SNAQ score decreased in all from 99.31 to 16.04. Mean Forced Expiratory Volume in the 1st second (FEV1) significantly improved after surgery from 3.23 to 3.45 L/s. CONCLUSIONS: ESS achieved a beneficial effect on upper and lower airway status in patients with chronic rhinosinusitis with or without lower airway diseases.

Crizotinib-induced immunogenic cell death in non-small cell lung cancer.

Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulates antitumor immune responses. Here we unravel the results of an unbiased screen identifying high-dose (10 µM) crizotinib as an ICD-inducing tyrosine kinase inhibitor that has exceptional antineoplastic activity when combined with non-ICD inducing chemotherapeutics like cisplatin. The combination of cisplatin and high-dose crizotinib induces ICD in non-small cell lung carcinoma (NSCLC) cells and effectively controls the growth of distinct (transplantable, carcinogen- or oncogene induced) orthotopic NSCLC models. These anticancer effects are linked to increased T lymphocyte infiltration and are abolished by T cell depletion or interferon-γ neutralization. Crizotinib plus cisplatin leads to an increase in the expression of PD-1 and PD-L1 in tumors, coupled to a strong sensitization of NSCLC to immunotherapy with PD-1 antibodies. Hence, a sequential combination treatment consisting in conventional chemotherapy together with crizotinib, followed by immune checkpoint blockade may be active against NSCLC.

Author Correction: Crizotinib-induced immunogenic cell death in non-small cell lung cancer.

The original version of this Article contained an error in the spelling of the author Lin Xia, which was incorrectly given as Xia Lin. This has now been corrected in both the PDF and HTML versions of the Article.

Immunotherapeutic properties of chemotherapy.

Impressive remissions driven by immunological checkpoint blockade in cancer patients have prompted the scientific community to investigate afresh the crosstalk between cancer cells and the patient's immune system. Preclinical and clinical studies have highlighted that the anticancer efficacy of some conventional chemotherapeutics is based on their ability to restore anticancer immune responses. The current challenge is to understand and circumvent immune resistance mechanisms to chemo- and immunotherapies to design relevant immunotherapy and chemotherapy combinations. In this review, we will summarize which immunological processes are involved in the anticancer action of some cytotoxic agents and discuss the recently unraveled contribution of the gut microbiota into the immunogenicity of anticancer drugs. We will eventually introduce the scientific rationale for therapeutic strategies combining chemotherapeutic drugs and immune checkpoint blockers.

Influence of metals on rhinosinusal polyposis in Sardinian population (Italy).

Metals have strong toxic effects in humans and can act as immunoregulatory factors. The purpose of our study was to determine whether the concentrations of metals are associated with the clinical course of nasal polyposis (NP). We measured the concentrations of 10 metals and non-metal (Zn, Mn, Se, Fe, Cr, Ni, Pb, Al, Cd, and Cu) in 58 patients with NP, and 29 controls with a healthy nasal mucosa. We used electron microscopy to compare the ultrastructural features of the nasal mucosa between NP patients and healthy controls. Concentrations of metals in nasal polyps and healthy mucosa were determined by mass spectrometry. Transmission electron microscopic (TEM) and scanning electron microscopic (SEM) images of the nasal mucosa were obtained. The mean tissue concentrations of all 10 metals and non-metal were significantly lower in NP patients than in healthy controls (P < 0.05).TEM and SEM revealed changes in the mucosal ultrastructure in NP with progressive fibrosis, devascularisation, and inflammation. Tissue concentrations of metals were lower in NP patients than in healthy controls, and this was particularly evident in massive polyposis.

HPV Type 6 and 18 Coinfection in a Case of Adult-Onset Laryngeal Papillomatosis: Immunization with Gardasil.

Laryngeal papillomatosis (LP) is a rare human papillomavirus (HPV) related disease that often requires multiple surgical interventions and residual impairment of voice is almost inevitable. We report the case of a patient with adult onset recurrent LP, showing moderate dysplasia and coinfection with HPV types 6 and 18. The tetravalent HPV vaccine Gardasil was prescribed off label, with the aim of triggering an immunogenic response and consequently reducing the probability of further recurrences. The patient was followed for 9 months with no sign of relapse of his LP. The postexposure use of the anti-HPV vaccine could represent a promising therapeutic agent in established LP. Unfortunately, the potential efficacy of this new therapeutic option in this situation has been suggested only by isolated case reports. Further controlled studies, with a longer follow-up and a larger sample size, are needed to assess efficacy of Gardasil in LP.

Comparison of three different polyvinyl alcohol packs following functional endoscopic Nasal surgery.

OBJECTIVES/HYPOTHESIS: To compare the extent of bleeding and patient discomfort during packing removal of three different polyvinyl alcohol (PVA) packs: 1) a standard PVA sponge (s-PVA) (Mondocel Standard 10 cm; Mondomed NV, Hamont-Achel, Belgium); 2) a PVA sponge with oxidized cellulose (oc-PVA) (Merocel Hemox 10 cm; Medtronic Xomed Surgical Products, Jacksonville, FL); and 3) a PVA sponge with polyethylene film (pf-PVA) (Merocel 2000 8 cm; Medtronic Xomed Surgical Products, Jacksonville, FL), after functional endoscopic sinus surgery and inferior turbinoplasty. STUDY DESIGN: A prospective, randomized, blinded, controlled trial. METHODS: Ninety consecutive patients were enrolled and randomized to receive in each side one pack in the middle meatus and another pack of the same material in the nasal fossa. The patients were equally divided in three groups of 30 patients each. Group A received the pf-PVA; group B received oc-PVA; and group C received s-PVA. Postoperatively, bleeding after removal of the entire nasal packing was evaluated by an observer, whereas the severity of pain was rated by patients with visual analog scales. RESULTS: Our study evaluated three nasal packing materials, demonstrating that the pf-PVA is less painful than the others but with intermediate bleeding ratio. However, the oc-PVA has an intermediate pain score but minimum bleeding. The s-PVA showed the worst pain and bleeding results. CONCLUSIONS: Considering that removal of the second pack (middle meatus) is more painful than the first (nasal fossa), our results suggest that a pf-PVA can be placed in the middle meatus and a oc-PVA in the nasal fossa in order to reduce patient's discomfort in terms of pain and bleeding. LEVEL OF EVIDENCE: 1b.

Pediatric follicular dendritic cell sarcoma of the head and neck: a case report and review of the literature.

OBJECTIVE: Follicular dendritic cell sarcoma is a rare disease with a non-specific and insidious presentation that is further complicated by difficult diagnostic and therapeutic assessment. METHODS: The database PubMed was searched for reports of follicular dendritic cell sarcoma between 1986 (first case published) and 2012. All of the articles presenting informations regarding one or more cases of follicular dendritic cell sarcoma of the head and neck region, in patients less than 18 years of age, were included. The reference lists for pertinent reports were also scanned to ensure that all relevant literature was included. RESULTS: We present a case of a 14 year-old girl, with a 2-month history of a right-sided level II neck mass. After a carefull radiologic evaluation the mass was resected combined with a right selective neck dissection. Histology with immunohistochemical staining was positive for follicular dendritic cell sarcoma. No recurrence was seen after 31 months follow-up. The literature search identified six more cases of pediatric follicular dendritic cell sarcoma of the head and neck. This is the first female patient with follicular dendritic cell sarcoma in the pediatric population. CONCLUSIONS: Current treatment of head and neck follicular dendritic cell sarcoma consists of wide radical resection, with associated radiotherapy or chemotherapy only for cases with aggressive disease such as extracapsular invasion, tumor size ≥6 cm or after failure of the first-line surgical treatment.