透明细胞肾细胞癌中人类内源性逆转录病毒的去抑制：对免疫治疗的意义.pdf

1、Qinqin Jiang,PhDKaelin LabDana-Farber Cancer InstituteHIF Regulates Multiple Translated Endogenous Retroviruses in ccRCC:Implications for ImmunotherapyccRCC “Immunogenic Tumor”Occasionally regress spontaneously Exhibit high level of T cell infiltration Respond to immune modulators,such as IL-2,IFN a

2、nd ICB despite modest mutation/neoantigen loadIt is unclear what tumor antigen(s)cause the apparent immunogenicity of ccRCCHREGagProPolEnv5LTR3LTRHIF2ERVE-4Endogenous Retroviruses(ERVs)and ccRCC One ccRCC patient who achieved a complete response following allogeneic stem cell transplantation harbore

3、d RCC-specific CD8+T cells that recognized a 10mer peptide derived from ERVE-4 ERVE-4 is an immunogenic ERV whose expression is driven by HIF2Takahashi et al,J.Clin.Invest.,2008Cherkasova et al,Cancer Res.,2016Identification of HIF-Regulated ERV PeptidesRNA-seq and Polysome-seq identified 81 HIF-reg

4、ulated ERVs at transcriptional and translational levelsHLA-IP/MS detected 34 ERV-derived peptides in ccRCC cells and patient tumorsImmunogenicity?Patient-Derived PBMCs Respond to KLI PeptidePBMCs from allo-SCT Responders Recognized 3 PeptidesResponders to ICIs Harbor T cells that Recognize ERVsTscan

5、 TherapeuticsTCRs:Identified from TILs of ICI responsive ccRCC tumorsTarget cells:Express 90-mers that derive from coding genes and ERVsERVE-4Summary and Future Directions Over-express tagged common HLA alleles to systematically identify HIF-regulated ERV peptides Characterize TCRs recognizing immun

6、ogenic ERV-derived peptidesAcknowledgementWilliam KaelinStirling ChurchmanNicholas KramerSteven CarrKarl ClauserJenn AbelinIsabelle LippincottCatherine Wu Derin Keskin Joseph Duke-Cohan Vipheaviny Chea Allison Vanasse Cleo FormanDavid Braun