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868 PRELP-Facilitated Enhancement of MHC Class I Surface Expression

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868 PRELP-Facilitated Enhancement of MHC Class I Surface Expression Abstracts J Immunother Cancer: first published as 10.1136/jitc-2020-SITC2020.0868 on 10 December 2020. Downloaded from fibroblasts (NAFs). NAFs/CAFs were then co-cultured with Methods We explored the TCGA-SKCM dataset and stratified healthy allogeneic PBMCs and their immunosuppressive prop- patients to distinct subgroups of cytolytic activity. We calcu- erties were assessed by flow cytometry. lated the tumor immune contexture, somatic mutations, recur- Results CAFs significantly supressed the proliferation of CD8+ rent copy number aberrations, chromothripsis, cancer and CD4+ T-cells and induced a more exhausted T-cell phe- neoepitopes, immunophenoscore, mutational signatures, katae- notype as evidenced by increased expression of the exhaustion gis and strand asymmetry in each cytolytic subgroup. markers TIM-3, LAG-3 and PD-1 when compared to co-cul- Results CYT was higher in enriched in immune-related gene ture with control NAFs, thereby demonstrating their potent sets metastatic tumors. Distinct mutational and neoantigen immunosuppressive properties. Strikingly, CAFs also induced loads, primarily composed of C>T transitions, along with significantly higher expression of both Siglec-7 and Siglec-9 specific types of copy number aberrations, characterized receptors on CD8+ T-cells specifically. each cytolytic subgroup. More chromothripsis events were To elucidate the role of sialylation on CAF-mediated found across CYT-low tumors SBS7a/b, SBS5 and SBS1 immunosuppression, NAFs/CAFs were treated with the sialyl- were the most prevalent mutational signatures in both cyto- transferase inhibitor (SI) P-3FAX-Neu5Ac prior to co-culture. lytic subgroups, but SBS1 differed significantly between Reduction of sialic acid expression on NAFs/CAFs was con- them. SBS7a/b were mutually exclusive with SBS5 and SBS1 firmed by flow cytometry and the SI-treated NAFs/CAFs in both CYT subgroups. Mutational strand asymmetries were then co-cultured with allogeneic T-cells to assess the related to the processes of DNA transcription and replica- functional consequences of reduced NAF/CAF sialylation. SI- tion differed between CYT-high and CYT-low tumors. CYT- treated CAFs induced significantly less CD4+TIM-3+ and high patients had markedly higher immunophenoscore and both CD4+LAG-3+ and CD8+LAG-3+ T-cells compared to should consequently, display an expected clinical benefit their untreated counterparts. Interestingly, SI-treated CAFs compared to CYT-low patients who either received or not, also induced significantly less Siglec-7 and -9 receptor- ICI. expressing CD8+ T-cells. Conclusions Our data highlight the existence of distinct genomic Conclusions These results demonstrate that non-haematopoietic features across cytolytic subgroups in skin melanoma patients, stromal cells in the tumour-microenvironment can suppress which could affect their relapse rate or resistance to ICI. activated T-cells and that this immunosuppressive effect can be significantly reversed through the modulation of sialylation on http://dx.doi.org/10.1136/jitc-2020-SITC2020.0867 the stromal cell surface. These results support the hypothesis that stromal cell sialylation plays a role in their immunosup- pressive properties. Understanding how sialylation of stromal copyright. cells is regulated and functions to enhance immunosuppression 868 PRELP-FACILITATED ENHANCEMENT OF MHC CLASS I in the TME could uncover novel immune checkpoints to reac- SURFACE EXPRESSION IN B16F10 MELANOMA CELLS tivate anti-tumour immunity, allowing for tumour cell Helene Schäfer*, Karthikeyan Subbarayan, Barbara Seliger. Martin-Luther-University Halle- clearance. Wittenberg, Medical Faculty, Halle (Saale), Germany Ethics Approval This study was approved by Galway Univer- sity Hospitals’ Clinical Research Ethics Committee, approval Background PRELP (proline arginine-rich end leucine-rich number C.A 2074. repeat protein; also Prolargin), a small leucine-rich proteogly- Consent N/A can, functions as a molecule anchoring basement membranes to connective tissues via the interaction with collagens and REFERENCES heparin. PRELP facilitates the binding of cells to glycosami- 1. Wang L, Liu Y, Wu L, Sun XL. Sialyltransferase inhibition and recent advances. noglycans as an important regulator of cell adhesion and http://jitc.bmj.com/ Biochim Biophys Acta 2016 Jan;1864(1):143-53. 2. Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines thus displays pathophysiological features. Melanoma is an (Basel) 2019 Oct 13;6(4):102. immunogenic tumor, whose relationship with immune cells resident in the microenvironment significantly influences can- http://dx.doi.org/10.1136/jitc-2020-SITC2020.0865 cer cell proliferation, progression and metastasis. Evasion from immune surveillance is a hallmark of melanoma pro- gression. While our laboratory reported that the proteoglycan biglycan (BGN) was enhancing MHC class I in tumor cells,1 on September 25, 2021 by guest. Protected 867 DISTINCT GENOMIC FEATURES ACROSS CYTOLYTIC the role of PRELP in tumor immunology has not been SUBGROUPS IN SKIN MELANOMA studied. Methods The murine metastatic melanoma cell line B16F10, 1Apostolos Zaravinos*, 2Constantinos Roufas, 3Ilias Georgakopoulos-Soares. 1Qatar University; 2European University Cyprus, Nicosia, Cyprus; 3University of California, San characterized by a reduced expression of MHC class I sur- Francisco, San Francisco, CA, USA face antigens was chosen for this study. B16F10 cells were transiently transfected with PRELP as well as co-transfected Background Skin melanoma is a highly immunogenic cancer. with BGN. Expression of antigen processing machinery The intratumoral immune cytolytic activity (CYT) reflects (APM) components and PRELP was determined by qPCR the ability of cytotoxic T cells and NK cells to eliminate and MHC class I surface expression by flow cytometry. Pro- cancer cells, and is associated with improved patient sur- moter activity of APM components was analysed by lucifer- vival. Despite the enthusiastic clinical results seen in ase reporter assays. XTT assays were used to determine cell advanced-stage metastatic melanoma patients treated with proliferation. The association of PRELP and MHC class I immune checkpoint inhibitors (ICI), a subgroup of them was studied by bioinformatics in a mixed melanoma dataset will later relapse and develop acquired resistance. We ques- of 83 samples.2 tioned whether CYT associates with different genomic pro- Results Over-expression of PRELP in B16F10 cells enhanced files in skin melanoma. the expression of MHC class I surface antigens, which was J Immunother Cancer 2020;8(Suppl 3):A1–A559 A515 Abstracts J Immunother Cancer: first published as 10.1136/jitc-2020-SITC2020.0868 on 10 December 2020. Downloaded from due to a PRELP-mediated transcriptional upregulation of such as the Erk1/2 and JNK pathways. Thus, LunX promoted components of the MHC class I APM components TAP1, tumor growth and metastasis. TAP2 and TAPBP as determined by qPCR and promoter Furthermore, we generated a therapeutic antibody specific assay in PRELP transfectants versus mock controls. Further- for lung cancer, which not only inhibited lung cancer growth more, MHC class I surface expression was even more pro- and reduced Ki67 staining and angiogenesis in xenograft nounced upon BGN co-transfection with PRELP. PRELP model of subcutaneously transplanted tumor, but also blocked overexpression was able to inhibit the proliferation of the tumor metastasis and invasion, improved the survival of these B16F10 cells. Bioinformatics analyses demonstrated a positive mice. We also detected that antibody treatment induces LunX correlation of PRELP with HLA-A , -B and -C alleles in antigen-antibody complex endocytosis and the degradation of human melanoma. LunX protein. Conclusions Our findings demonstrated that overexpression of Conclusions Our study suggests that LunX is a novel thera- PRELP correlates with higher MHC class I expression and peutic target in lung cancer and that the LunX-targeted thera- inhibits cell proliferation. For the first time, co-transfections of peutic antibody may have considerable clinical benefit. the two proteoglycans PRELP and BGN had a synergistic http://dx.doi.org/10.1136/jitc-2020-SITC2020.0869 effect on upregulating MHC class I expression. Therefore, PRELP can serve as a novel therapeutic strategy that deserves further investigation. Acknowledgements The project is supported by Wilhelm- 870 INVESTIGATING SEXUAL DIMORPHISM IN THE TUMOR Sander-Stiftung (No: 2019.076.1) and by a Roux grant (FKZ: IMMUNE MICROENVIRONMENT OF NON-MUSCLE PK37) of the Medical Faculty of the Martin-Luther-University INVASIVE BLADDER CANCER Halle-Wittenberg. 1Stephen Chenard*, 1Chelsea Jackson, 2Thiago Vidotto, 1Celine Hardy, 1 1 3 1 1 ’ REFERENCES Tamara Jamaspishvilli, David Berman, David Robert Siemens, Madhuri Koti. Queen s University, Kingston, ON, Canada; 2Johns Hopkins School of Medicine, Baltimore, MD, USA; 1. Subbarayan K, Leisz S, Wickenhauser C, Bethmann D, Massa C, Steven A, Seliger 3 B. Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-trans- Kingston Health Sciences Centre, Kingston, Canada formed cells. Oncoimmunology 2018;7:e1373233. 2. Xu L, Shen SS, Hoshida Y, Subramanian A, Ross K, Brunet JP, Wagner SN, Ram- Background While the incidence of non-muscle invasive blad- aswamy S, Mesirov JP, Hynes RO. Gene expression changes in an animal mela- der cancer (NMIBC) is four times higher in men than women, noma model correlate with aggressiveness of human melanoma
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