Low Concordance Between T-Cell Densities in Matched Primary Tumors and Liver Metastases in Microsatellite Stable Colorectal Cancer.

Vegar Johansen Dagenborg,Anne Hansen Ree,Marius Lund-Iversen,Sheraz Yaqub,Krzysztof Grzyb,Serena Elizabeth Marshall,Gunhild Mari Mælandsmo,Kjersti Flatmark,Åsmund Avdem Fretland,Bjørn Edwin

doi:10.3389/fonc.2021.671629

Abstract

BackgroundThe subtype, density and location of tumor infiltrating T-cells are being explored as prognostic and predictive biomarkers in primary colorectal cancer (pCRC) and colorectal liver metastases (CLM). Very limited data exist comparing findings in pCRC and matched CLM.Patients and methodsFifty-eight patients with available pCRC and matched CLM (57/58 microsatellite stable) were included in this OSLO-COMET substudy. In immunohistochemically stained sections, total (Ttot), helper (TH), cytotoxic (CTL), and regulatory (Treg) T-cells were manually counted in hotspots from the invasive margin (IM), intratumor (IT), and tumor adjacent regions to determine T-cell densities.ResultsA striking accumulation of T-cells was found in IM of both pCRC and CLM with much lower densities in the IT region, exemplified by Ttot of 2838 versus 340 cells/mm2, respectively, in CLM. The correlation at the individual level between T-cell densities in pCRC and corresponding CLM was poor for all regions and T-cell subtypes; for instance, the correlation coefficient (R2) for IM Ttot was 0.07. The IT TH : CTL and Treg : TH ratios were 2.94 and 0.44, respectively, in pCRC, and 1.84 and 0.24, respectively, in CLM.ConclusionThe observed accumulation of T-cells in the IM regions of pCRC and CLM with low penetration to the IT regions, combined with high TH : CTL and Treg : TH ratios, point to the presence of an immune suppressive microenvironment. T-cell densities of CLM differed markedly from the matched pCRC, indicating that to evaluate T-cell biomarkers in metastasis, the commonly available pCRC cannot serve as a surrogate for the metastatic tumor.

Highlights

Colorectal cancer (CRC) is one of the most frequent cancers in the western world and about 50% of CRC patients will develop metastases during the course of disease, with the liver as the most frequent metastatic site [1, 2]
Thirteen cases were excluded from analysis because of unavailable or insufficient tumor content in the primary colorectal cancer (pCRC) (n = 6) and colorectal liver metastases (CLM) sample (n = 7), leaving 58 patients with pCRC tissue and corresponding CLM
For analyses related to outcome and immune score mean values were used for patients with multiple metastases, as we previously demonstrated that the variation in T-cell densities between metastases from the same patients was very low [6]

Summary

Introduction

Colorectal cancer (CRC) is one of the most frequent cancers in the western world and about 50% of CRC patients will develop metastases during the course of disease, with the liver as the most frequent metastatic site [1, 2]. The therapeutic opportunities have improved dramatically over the last two decades for patients with metastatic CRC (mCRC), the successes derived from introduction of immunotherapy have so far only been beneficial to microsatellite instable (MSI) cases, comprising approximately 5% of patients with mCRC [4]. It is of high interest to understand the non-immunogenic cancers, such as microsatellite stable (MSS) CRC, to potentially identify opportunities to circumvent resistance and make immunotherapy a therapeutic option for the majority of mCRC patients [5]. We recently showed up-regulation of immune-related genes and increased T-cell infiltration in colorectal liver metastases (CLM) after neoadjuvant chemotherapy, suggesting that cytotoxic therapies might favorably modify the tumor microenvironment to become more immunologically active [6, 7]. Very limited data exist comparing findings in pCRC and matched CLM

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