Prognostic value of tumor-infiltrating immune cells in patients with colorectal cancer

Currently, the treatment of advanced colorectal cancer (CRC) differs and oncologists face complicated decisions in the choice of the most suitable treatment options for their patients. Predictive and prognostic biomarkers can simplify clinical decision making. Prognostic factors are those parameters that separate a population in terms of their clinical outcome in the absent of treatment. Predictive factors are those that identifies patients base on clinical outcome in response to particular treatment or lack of response to specific treatment (1,2). Validation of prognostic markers can be performed by data from a retrospective series of patients treated with standard cares. However, analysis of quality randomized clinical trials (RCTs) use for validation of predictive markers (2). Histopathological characteristics such as: the size of the tumor, atypical cell morphology, aberrant expression of protein and recently genetic markers applied to estimate the patient prognosis or predict clinical outcome. In addition, average disease-free survival (DFS), disease-specific survival (DSS), overall survival (OS) or other available statistical data are used for the estimation (3).

Surgical resection is potentially curative for CRC, but Local Recurrences and Distant Metastases progress in 40% of patients (4). At present, the classification of CRC is based on several clinicopathologic factors, including depth of invasive, presence of lymph node metastasis and distant metastasis, which is called tumor node metastases (TNM) staging. Recently, the host lymphoid response to the tumor was included among variables that have shown to be favorable prognostic factors, but translation of knowledge from basic science into daily diagnostic practice is one of the major challenges in routine pathologic reports (5).

From an immunologist’s point of view, cytotoxic T lymphocytes (CTLs), classically CD8 T cells can more reliably be considered as a symbol of a systemic anti-tumor immune response (6).

To gain insight use this new variable, several studies were done. These studies show that, the anatomic location of immune cell within the tumor tissue (i.e., intraepithelial, stromal, or advancing border) is very important in this issue and correlates with clinical outcome (7-10). Infiltrating T lymphocytes in direct contact with tumor cells, are often referred to as tumor-infiltrating lymphocytes (TIL), are believed to be directly related to the antitumor immune response. Guidoboni and their colleagues documented that, the presence of CD8 T cells in peri-tumoural and stromal was not correlated with improved prognosis, while the presence of intra-epithelial CD8 T cells was associated with better survival independently of pathological stage (6). Naito et al. show that, CD8 T cells infiltrated within cancer cell nets can be a prognostic factor to predict a longer survival of CRC patients (11).

Numerous reports have suggested a correlation between microsatellite instability (MSI), formal Genetic prognostic and predictive marker, and TIL (12-14). According the site of lymphocyte infiltration, TIL can be separated into two types: stromal infiltrating lymphocytes (SIL) and intra-tumor-cell infiltrating lymphocytes (ITCIL). In some previous reports (15-18) the distinction between SIL and ITCIL was not clear. Surely, when dividing TIL into SIL and ITCIL, it is clinically important to determine which type is more closely related to MSI and which is more useful as a survival and recurrence indicator. Takemoto et al. showed that SIL consisted of a variety of lymphocytes such as: CD4-, CD8- and S-100-positive cells, while ITCILs primarily consisted of CD8-positive cells. This study strongly suggests that different factors are involved in the infiltration of SIL and ITCIL, and that intra-tumor cell-infiltration of lymphocytes is caused by MSI (19). A meta-analysis report by Huang et al. suggested that, tumor-infiltrating Forkhead box protein P3 (FoxP3) T cells, a transcription factor necessary and sufficient for induction of the immunosuppressive functions of regulatory T cells (Tregs), were a factor for a poor prognosis for HCC and GC, but a good prognosis for CRC (20).

Väyrynen et al. show that quantitative evaluation of Crohn’s like lymphoid reaction (CLR) density, an inflammatory reaction pattern that consists of numerous transmural lymphoid aggregates, is a relevant prognostic indicator in CRC (21).

In conclusion, data accumulated support the hypothesis that cancer progress is influenced by the host immune system and the presence of immune cells with tumor-suppressive and tumor-promoting activity in the cancer microenvironment and in peripheral blood is usually associated with good clinical outcomes and poor clinical outcomes, respectively (22). New cancer classification using the immunoscore, demonstrating the prevalence of immune infiltrates, has a prognostic significance exceeding that of the TNM classification system. In other words, multivariate Cox analysis have revealed that, the immune criteria remained highly significantly associated with prognosis for all CRC patients (stage I/II/III) (23).

Acknowledgements

Disclosure: The authors declare no conflict of interest.

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