Histologic-Based Tumor-Associated Immune Cells Status in Clear Cell Renal Cell Carcinoma Correlates with Gene Signatures Related to Cancer Immunity and Clinical Outcomes.

Chisato Ohe,Yoshiki Yasukochi,Naho Atsumi,Toyonori Tsuzuki,Koichiro Higasa,Hidefumi Kinoshita,Riuko Ohashi,Ryoichi Saito,Ryosuke Yamaka,Junichi Ikeda,Koji Tsuta,Haruyuki Ohsugi,Takashi Yoshida

doi:10.3390/biomedicines10020323

Abstract

The three-tier immunophenotype (desert, excluded, and inflamed) and the four-tier immunophenotype (cold, immunosuppressed, excluded, and hot) have been linked to prognosis and immunotherapy response. This study aims to evaluate whether immunophenotypes of clear cell renal cell carcinoma, identified on hematoxylin and eosin-stained slides, correlate with gene expression signatures related to cancer immunity, and clinical outcomes. We evaluated tumor-associated immune cells (TAICs) status using three methodologies: three-tier immunophenotype based on the location of TAICs, four-tier immunophenotype considering both the location and degree of TAICs and inflammation score focusing only on the degree of TAICs, using a localized clear cell renal cell carcinoma cohort (n = 436) and The Cancer Genome Atlas (TCGA)-KIRC cohort (n = 162). We evaluated the association of the TAICs status assessed by three methodologies with CD8 and PD-L1 immunohistochemistry and immune gene expression signatures by TCGA RNA-sequencing data. All three methodologies correlated with immunohistochemical and immune gene expression signatures. The inflammation score and the four-tier immunophenotype showed similarly higher accuracy in predicting recurrence-free survival and overall survival compared to the three-tier immunophenotype. In conclusion, a simple histologic assessment of TIACs may predict clinical outcomes and immunotherapy responses.

Highlights

The current study aims to evaluate whether immunophenotypes of clear cell RCC (ccRCC), identified on hematoxylin and eosin (H&E)-stained slides, correlated with the gene expression signature related to cancer immunity, and clinical outcomes
We found that the four-tier immunophenotype considering both the location and degree of tumor-associated immune cells (TAICs) was more highly correlated with gene expression signatures related to cancer immunity compared to the three-tier immunophenotype based on the location of TAICs
Regarding the association of pathological prognostic factors, we found that a dedifferentiation form of ccRCC, such as sarcomatoid/rhabdoid, was significantly correlated with inflammation score 3, followed by score 2, which corresponded with the enrichment of immune checkpoint signatures

Summary

Introduction

The prognosis of metastatic renal cell carcinoma (RCC) has improved by the efficacy of immune checkpoint inhibitors (ICIs) such as agents directed against cytotoxic. Comprehensive genomic investigations have provided a biology-based tumor immune microenvironment for treatment selection using genomic and transcriptomic analysis [3,4,5]. Biomedicines 2022, 10, 323 clear cell RCC (ccRCC) to evaluate their potential predictive value of TKIs, ICIs alone, or in combination, for patients with metastatic RCC revealed the association of gene expression signatures related to angiogenesis, effector T-cell, and myeloid inflammation with clinical outcome [6,7]. A simple histologic-based assessment of the tumor immune microenvironment is urgently needed. The prognostic and predictive value of TILs for RCCs remains under investigation

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