Background: We previously reported that increased infiltration of immune cells (lymphocytes, plasma cells, macrophages, neutrophils) in localized ccRCC is associated with recurrence. In these tumors we now study the immune gene expression to identify a signature to predict recurrence.
Methods: We identified pts with ccRCC with >T1b tumor who underwent nephrectomy for whom we had annotation for objective tumor recurrence and a minimum follow-up of 2 years. All histologic slides were examined and tumor section with the highest amount of intratumoral immune infiltration were selected from each tumor for gene expression profiling. Total mRNA isolated from the macrodissected FFPE tumor underwent gene expression profiling for 770 genes in the Immune Profile Panel by NanoString Technologies. Digital raw counts of mRNA abundance were normalized using positive controls as well as 16 housekeeping genes. The mean signals were used to calculate fold change in gene expression between recurrers and non-recurrers, and a p-value <0.05 using empirical Bayes methods was considered significant. Cox regression was also conducted to correlate gene expression with time to recurrence.
Results: Of 132 patients (pts), 24 (18%) had recurrence and 108 did not. The median age of pts was 59 years and 57 were female. The median time to recurrence was 25.7 months. Fifty pts had low immune infiltration score and 82 pts had high infiltration based on previously conducted morphologic assessment. Only 4 genes (IL8, NCAM1, ARG2, PPBP) had >1.5 times increased mean expression in recurrers vs non-recurrers (p<0.05). Only 5 genes (CX3CL1, HLA-G, VCAM1, IL17RB, CXCL14) had >1.5 times decreased mean expression in recurrers vs non-recurrers (p<0.05). Overexpression of the following immunoregulatory genes was associated with a shorter time to recurrence: TGFB1, STAT3, NFATC4, B7-H3, ADORA2A, OX-40L, IL10, RUNX1, LILRA4, MARCO, CR1, FCER2, IL2RA (HR 1.5-3.6, p<0.05). When compared to pts with low lymphocyte infiltration, pts with high lymphocyte infiltration overexpressed T cell (CD3E, CD5), cytotoxic T cell (CD8B, SLAMF6, IL2RB, GZMK, TCF7, CTSW, EBI3), Th1 (CD38, CXCR3, CXCR6, IL16), Th2 (ITK) and Tregs (IL2RB, IRF4, TIGIT) genes (FDR p<0.01).
Conclusions: Specific immune related somatic genes were differentially expressed based on recurrence and time to recurrence in patients with localized ccRCC undergoing surgery. With further validation, these genes warrant functional validation since they may represent therapeutic targets in the perioperative setting. The results also highlight the heterogeneity of immune cell infiltration.
Citation Format: Pooja Ghatalia, Karthik Devarajan, Jennifer Gordetsky, Essel Dulaimi, Sejong Bae, Gurudatta Naik, Guru Sonpavde, Elizabeth Plimack. Immune gene expression and prognosis in localized clear cell (cc) renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3141.