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Abstract
Background Clear cell renal cell carcinoma (ccRCC) patients with high toll-like receptor 3 (TLR3) gene expression have shown improved overall survival.1 However, the precise mechanism underlying this observation remains poorly understood. This study aimed to investigate the tumor immune microenvironment and its correlation with intratumoral TLR3 gene expression, as well as their associations with the response to immune checkpoint inhibitor (ICI) treatment.
Methods We retrospectively analyzed patients with ccRCC from the Total Cancer Care Program at the Ohio State University. Patients with available tumor RNA-Seq data, metastatic disease, clear cell histology, and immune checkpoint inhibitor (ICI) treatment were included. Matched tumor sections were analyzed using Vectra® Polaris™ multiplex immunofluorescence. The markers included CD3, CD8, FoxP3, GzmB, T-bet, PD-1, CD68, CD86, CD11c, CD11b, CD163, and pan-cytokeratin. Major responses (complete or partial responses) were determined by RECIST 1.1 criteria. Patients were divided into TLR3 gene expression high vs intermediate vs low groups based on the interquartile range. Treatment responses and immune cell densities were compared among the groups using Pearson’s chi-square and Kruskal Wallis Test.
Results Among the 25 patients who met the inclusion criteria, the major response rate was 50% for 6 patients with high TLR3 gene expression (>75th percentile), compared to 0% for 6 patients with low TLR3 gene expression (<25th percentile) (p=0.046). The major response rate for 13 patients with intermediate TLR3 gene expression (25th to 75th percentile) was 23%. Additionally, patients with high TLR3 gene expression had a significantly higher median intratumoral CD8+ T lymphocyte density (60 cells/mm2) compared to the intermediate (28 cells/mm2) and low (11 cells/mm2) TLR3 groups, as indicated by Kruskal Wallis test with p-value of 0.049 (figure 1). The comparisons of other immune cell densities were not statistically significant.
Conclusions High intratumoral TLR3 gene expression was associated with a higher rate of major responses in ccRCC patients treated with immune checkpoint inhibitors (ICIs). This correlation may be attributed to increased infiltration of CD8+ T lymphocytes. Future studies with larger cohorts are needed to confirm these findings.
Acknowledgements We acknowledge the invaluable support provided by the Pelotonia Institute for Immuno-Oncology (PIIO) Immuno Monitoring and Discovery Platform (IMDP) at the Ohio State University for our project. Their assistance has been instrumental in the successful execution of our research.
Reference
Li M, Z Li, P Kalinski, C Verschraegen, S Clinton, Y Yang, A Mortazavi, P Monk, E Folefac, M Yin, A Parikh, Y Yang. ‘156P High TLR3 expression predicts improved survival in patients with clear cell renal cell carcinoma.’ Annals of Oncology 2020;31:S301.
Ethics Approval This study (Study ID: 2020C0054) was reviewed and approved by the Institutional Review Board at the Ohio State University.
Patients with high TLR3 gene expression exhibited a significantly higher CD8 cell density compared to those with low TLR3 gene expression (p-value = 0.049, Kruskal-Wallis test). TLR3 denotes toll-like receptor 3.
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