Abstract
Clear cell renal cell carcinoma (ccRCC) has shown durable responses to checkpoint blockade therapies. However, important gaps persist in the understanding of its immune microenvironment. This study aims to investigate the expression and prognostic significance of immune checkpoints in primary and metastatic ccRCC, in relation with mature dendritic cells (DC) and T-cell densities. We investigated the infiltration and the localization of CD8(+) T cells and mature DC, and the expression of immune checkpoints (PD-1, LAG-3, PD-L1, and PD-L2) in relation with prognosis, in 135 primary ccRCC tumors and 51 ccRCC lung metastases. RNA expression data for 496 primary ccRCC samples were used as confirmatory cohort. We identify two groups of tumors with extensive CD8(+) T-cell infiltrates. One group, characterized by high expression of immune checkpoints in the absence of fully functional mature DC, is associated with increased risk of disease progression. The second group, characterized by low expression of immune checkpoints and localization of mature DC in peritumoral immune aggregates (tertiary lymphoid structures), is associated with good prognosis. The expression of the immune checkpoints and the localization of DC in the tumor microenvironment modulate the clinical impact of CD8(+) T cells in ccRCC.
Highlights
A solid tumor is an intricate and dynamic ecosystem containing tumor and immune cells, fibroblasts, blood, and lymphaticNote: Supplementary data for this article are available at Clinical Cancer Research Online.W.H
Tumor infiltration by CD8þ T lymphocytes and expression of Th1-associated genes correlate with poor prognosis in Clear cell renal cell carcinoma (ccRCC)
The density of CD8þ T cells in the Invasive Margin (IM) of the primary tumors was heterogeneous in the cohort of 135 primary ccRCC
Summary
A solid tumor is an intricate and dynamic ecosystem containing tumor and immune cells, fibroblasts, blood, and lymphaticNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).W.H. A solid tumor is an intricate and dynamic ecosystem containing tumor and immune cells, fibroblasts, blood, and lymphatic. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The density and composition of the immune microenvironment is heterogeneous among patients and tumor types, and it is becoming a robust tool to predict postsurgical recurrence and death [1, 2]. In the vast majority of cancers, tumor infiltration by CD8þ memory cytotoxic T cells and Th1 cells is associated with good clinical outcome [1]. It has been reported that an organized local immune reaction, characterized by the presence of mature dendritic cells (DC)
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