Michor, FranziskaNovina, CarlZhang, Cheng-ZhongMonti, StefanoMeng, Yuzhong2019-12-112019-112019-08-282019Meng, Yuzhong. 2019. Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.http://nrs.harvard.edu/urn-3:HUL.InstRepos:42013164Immunotherapies such as checkpoint blockade have improved response and survival in patients with metastatic melanoma. Tumor-infiltrating lymphocyte (TIL) therapy, a treatment that uses T cells extracted from patients’ own tumor tissue to increase anti-tumor immune response, produces response rates of 40–60% in melanoma, on par with combined anti-CTLA4 and anti-PD1 checkpoint blockade. However, the determinants of response and mechanisms of resistance to TIL therapy are largely unknown. Here we report that predicted MHC class I neoantigen load correlates with overall survival (OS), but does not correlate significantly with progression-free survival (PFS) or RECIST response. In addition, mutations in PRRT2 correlate with short OS and short PFS. Somatic copy number alterations (SCNAs) in seven genomic regions correlate with PFS. Transcriptional data show PDE1C, RTKN2, and NGFR to be enriched in long OS, long PFS, and response, whereas ELFN1 is enriched in short OS, short PFS, and lack of response. Comparison of pre-treatment and post-treatment samples reveals dozens of differentially expressed genes, as well as changing clonal dynamics. Taken together, our findings suggest that melanoma control by TIL therapy correlates with neoantigen load, specific mutations, SCNAs, and tumor transcriptional state. We also provide evidence for cancer adaptation to TIL therapy.application/pdfenMelanomagenomicscancer genomicsimmunotherapytumor-infiltrating lymphocytes.Thesis or Dissertation2019-12-11