Regulatory T Cell Infiltration Predicts Outcome Following Resection of Colorectal Cancer Liver Metastases

Abstract

Background Tumor-infiltrating lymphocyte (TIL) counts in colorectal cancer liver metastases (CRCLM) predict survival following resection. While CD4 and CD8 T cells have been correlated with outcome following CRCLM resection, the role of regulatory T cells (Treg) is not well defined. Methods TIL in 188 patients who underwent CRCLM resection between 1998 and 2000 were analyzed by immunohistochemistry using tissue microarrays. Correlation between TIL composition and outcome was determined while controlling for established prognostic factors. Total T cells (CD3), helper T cells (CD4), cytotoxic T cells (CD8), and Treg (FoxP3) were analyzed. Results Median follow-up time was 40 months for all patients and 95 months for survivors. Overall survival (OS) at 5 and 10 years was 40 and 25 %, respectively. The CD4 T cell count correlated with OS (p = .02) and recurrencefree survival (p = .04). A high number of CD8 T cells relative to total T cells (CD8:CD3 ratio) predicted longer OS times (p = .05). Analysis of Treg revealed that high FoxP3:CD4 (p = .03) and FoxP3:CD8 (p = .05) ratios were independent predictors of shorter OS. Patients with a high clinical risk score (CRS) were more likely to have a high number of intratumoral Treg, and patients ≥65 years old had a less robust CRCLM T cell infiltration. Conclusions A high number of Treg relative to CD4 or CD8 T cells predicted poor outcome, suggesting an immunosuppressive role for FoxP3 + TIL. The intratumoral immune response was an independent predictor of outcome in patients with colorectal liver metastases.

Comparative analysis of CD4 and CD8 lymphocytes — evidences for different distribution in primary and secondary liver tumors

“…Our results supplement the reports by other authors that support the positive prognosis value of CD8+ T lymphocytes in LM [33][34][35].…”

“…The review of the literature reveals attentiveness to the investigation of TILs in hepatic parenchyma, in primary tumor context -namely hepatocellular carcinoma (HCC) [3,[21][22][23][24][25][26][27][28][29][30][31][32] or in liver metastases (LM) [33][34][35]. Nevertheless, we have to highlight the fact that none of the published studies presented comparative data of CD4+ and CD8+ T lymphocytes in primary versus secondary liver tumors.…”

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…S2). Together, these data indicate that the CD8 + CTL:Treg ratio, which is critical for immunological tumor control in primary as well as metastasized CRC, 42 is more favorable in CRC metastases compared to primary CRC. In addition, the increased expression of PD-1 on TIL suggests that TIL of LM-CRC may be more sensitive to blockade of the PD-1/PD-L1 pathway than TIL of primary CRC.…”

Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy

“…Additionally, active mechanisms employed by colon cancer to evade immune recognition have been correlated with lower TIL infiltration and poorer clinical outcomes, such as downregulation of MHC class I (MHC-I) expression by cancer cells (20), and high levels of immunosuppressive molecules such as IDO1 found in the tumor microenvironment (21). In colorectal cancer metastatic to the liver (stage IV), longer survival of patients after complete resection of metastases has been associated with a higher density of CD4 + and CD8 + TILs in metastases and their relative abundance compared with FOXP3 + T cells (putative regulatory T cells [Tregs]) (22,23). However, in vitro evidence of MHCrestricted recognition of autologous GI cancers by TILs is limited.…”