Human Leukocyte Antigen-A Allele Distribution in Nasopharyngeal Carcinoma Patients Showing Anti-Melanoma-Associated Antigen A or Synovial Sarcoma X-2 T Cell Response in Blood

Background： Development of innovative immunotherapy is imperative to improve the poor survival of the nasopharyngeal carcinoma （NPC） patients. In this study, we evaluated the T cell response to melanoma-associated antigen （MAGE）-A1, MAGE-A3, or synovial sarcoma X-2 （SSX-2） in the peripheral blood of treatment-naive NPC patients. The relationship of responses among the three proteins and the human leukocyte antigen （HLA）-A types were analyzed to provide evidence of designing novel therapy. Methods： Sixty-one NPC patients admitted into the Tumor Hospital affiliated to the Xinjiang Medical University between March 2015 and July 2016 were enrolled. Mononuclear cells were isolated from the peripheral blood before any treatment. HLA-A alleles were typed with Sanger sequence-based typing technique. The T cell response to the MAGE-A1, MAGE-A3, or SSX-2 was evaluated with the Enzyme-Linked ImmunoSpot assay. Mann-Whitney U-test was used to compare the T cell responses from different groups. Spearman＇s rank correlation was used to analyze the relationship of T cell responses. Results： HLA-A＊02：01, A＊02：07, and A＊24：02 were the three most frequent alleles （18.9%, 12.3%, and 11.5%, respectively） among the 22 detected alleles. 31.1%, 19.7%, and 16.4% of the patients displayed MAGE-A1, MAGE-A3, or SSX-2-specific T cell response, respectively. The magnitudes of response to the three proteins were 32.5, 38.0, and 28.7 SFC/106 peripheral blood mononuclear cells, respectively. The T cell response against the three proteins correlated with each other to different extent. The percentage of A＊02：01 and A＊24：02 carriers were significantly higher in patients responding to any of the three proteins compared to the nonresponders. Conclusion： MAGE-A1, MAGE-A3, or SSX-2-specific T cell responses were detectable in a subgroup of NPC patients, the frequency and magnitude of which were correlated.

Diagnosis and treatment of autoimmune retinopathy

Autoimmune retinopathy(AIR)refers to both paraneoplastic and non-paraneoplastic forms of a rare,acquired retinal degeneration thought to be mediated by the production of antiretinal antibodies.However,the mechanisms underlying AIR pathogenesis are incompletely understood,and it remains a diagnosis of exclusion given the lack of definitive testing as well as its protean clinical presentation.This review summarizes the current literature on the epidemiology,diagnosis,and management of AIR,with a focus on non-paraneoplastic disease and the potential role of immunomodulatory therapy.A recent expert consensus statement on diagnosis and management of non-paraneoplastic AIR served as a framework for interpreting the limited data available,a process that was complicated by the small sample sizes,heterogeneity,and retrospective nature of these studies.Additional work is needed to characterize AIR patients on the basis of cytokine and immunogenetic profiling;to establish the pathogenicity of antiretinal antibodies;and to standardize treatment regimens as well as assessment of clinical outcomes.

MAGE-C3 promotes cancer metastasis by inducing epithelial-mesenchymal transition and immunosuppression in esophageal squamous cell carcinoma

Background:Evading immune surveillance is necessary for tumor metastasis.Thus,there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion.In this study,we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma(ESCC).Methods:The expression of melanoma-associated antigen C3(MAGE-C3)was detected using immunohistochemistry.Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma(ESCC)cells.Metastasis assays in mice were used to evaluate metastatic ability in vivo.Lymphocyte-mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells.RNA sequencing was performed to identify differentially expressed genes between MAGE-C3 overexpressing ESCC cells and control cells.Gene ontology(GO)enrichment analyses was performed to identify the most altered pathways influenced by MAGE-C3.The activation of the interferon-γ(IFN-γ)pathway was analyzed using Western blotting,GAS luciferase reporter assays,immunofluorescence,and flow cytometry.The role of MAGE-C3 in the IFN-γpathway was determined by Western blotting and immunoprecipitation.Furthermore,immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases.Results:MAGE-C3 was overexpressed in ESCC tissues.High expression of MAGE-C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC.Functional experiments revealed that MAGE-C3 promoted tumor metastasis by activating the epithelial-mesenchymal transition(EMT).MAGE-C3 repressed antitumor immunity and regulated cytokine secretion of T cells,implying an immunosuppressive function.Mechanistically,MAGE-C3 facilitated IFN-γsignaling and upregulated programmed cell death ligand 1(PDŋL1)by binding with IFN-γreceptor 1(IFNGR1)and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1(STAT1).Interestingly,MAGE-C3 displayed higher tumorigenesis in immune-competent mice than in immune-deficient nude mice,confirming the immunosuppressive role of MAGE-C3.Furthermore,mice bearing MAGE-C3-overexpressing tumors showed worse survival and more lung metastases with decreased CD8+infiltrated T cells and increased programmed cell death 1(PD-1)^(+)CD8^(+) infiltrated T cells.Conclusion:MAGE-C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance,and could be a potential prognostic marker and therapeutic target.