Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer.

Mercedes Herrera,Arne Östman,Carina Strell,Tobias Sjöblom,Christian Klein,Lisa Villabona,Bengt Glimelius,Giuseppe Masucci,Gabriele Hölzlwimmer,Sara Corvigno,Artur Mezheyeuski

doi:10.3390/cancers12113238

Abstract

Simple SummaryIn addition to malignant cells, tumors are composed also of other cell types including immune cells and fibroblasts. These cell types interact with each other and with the malignant cells. Prognosis associations have previously been demonstrated for CD8-positive immune cells. Recent studies suggest that fibroblasts can affect the function of immune cells. The aim of this study was to investigate if the fibroblast composition of tumors affected the prognosis association of CD8 immune cells. This study demonstrated that in colon cancer, CD8 prognosis associations was restricted to the group of tumors with high expression the FAP fibroblast marker. Our findings suggest continued mechanistic studies regarding crosstalk between FAP-positive fibroblasts and the different immune cell types; and also support the investigation of fibroblast/T-cell interactions for therapeutic purposes.Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

Highlights

The current classification of colorectal cancer (CRC) by the AJCC (American Joint Committee on Cancer) depends on the extent of the primary tumor (T), the involvement of regional lymph nodes (N)and the presence of distant metastases (M) (TNM staging) [1]
This study investigates the prognosis associations of fibroblast activation protein (FAP) and CD8a in two colon cancer cohorts and, explores the possibility that the prognostic capacity of CD8-positive cells differs between cases defined by their FAP status
Analyses were performed on tissue microarray (TMA) of colon cancers from the U-CAN population composed of patients diagnosed between 2010 and 2014 in Uppsala County, Sweden

Summary

Introduction

The current classification of colorectal cancer (CRC) by the AJCC (American Joint Committee on Cancer) depends on the extent of the primary tumor (T), the involvement of regional lymph nodes (N)and the presence of distant metastases (M) (TNM staging) [1]. TNM classification fails to provide sufficient prognostic information [2]. Immune cell infiltration has a major effect on the clinical outcome in solid tumors, and it has been associated with a favorable prognosis [3,4,5,6]. The integration of additional immune modulatory mechanisms might improve the prognostic significance of “immunoscore” or other markers related to T-cell enumeration. This notion is supported by emerging findings, including demonstrations that the prognostic capacity of an immunoscore-like metagene differing between cases with high or low expressions of checkpoint inhibitors [8]

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