The Prognostic Implications of Tumor Infiltrating Lymphocytes in Colorectal Cancer: A Systematic Review and Meta-Analysis

Abstract

Tumor-infiltrating lymphocytes (TILs) are an important histopathologic feature of colorectal cancer that confer prognostic information. Previous clinical and epidemiologic studies have found that the presence and quantification of tumor-infiltrating lymphocytes are significantly associated with diseasespecific and overall survival in colorectal cancer. We performed a systematic review and meta-analysis, establishing pooled estimates for survival outcomes based on the presence of TILs in colon cancer. PubMed (Medline), Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to April 2017. Studies were included, in which the prognostic significance of intratumoral tumor infiltrating lymphocytes, as well as subsets of CD3, CD8, FOXP3, CD45R0 lymphocytes, were determined within the solid tumor center, the invasive margin, and tumor stroma. Random-effects models were calculated to estimated summary effects using hazard ratios. Forty-three relevant studies describing 21,015 patients were included in our meta-analysis. The results demonstrate that high levels of generalized TILS as compared to low levels had an improved overall survival (OS) with a HR of 0.65 (p = <0.01). In addition, histologically localized CD3+ T-cells at the tumor center were significantly associated with better disease-free survival (HR = 0.46, 95% CI 0.36-0.61, p = 0.05), and CD3 + cells at the invasive margin were associated with improved disease-free survival (HR = 0.57, 95% CI 0.38-0.86, p = 0.05). CD8+ T-cells at the tumor center had statistically significant prognostic value on cancerspecific survival and overall survival with HRs of 0.65 (p = 0.02) and 0.71 (p < 0.01), respectively. Lastly, FOXP3+ T-cells at the tumor center were associated with improved prognosis for cancer-specific survival (HR = 0.65, p < 0.01) and overall survival (HR = 0.70, p < 0.01). These findings suggest that TILs and specific TIL subsets serve as prognostic biomarkers for colorectal cancer. Although advances in screening and treatment have substantially improved survival from colorectal cancer (CRC), clinical outcomes vary widely among patients with tumors diagnosed at the same TNM stage, and disease relapse occurs in 20-30% of patients with localized cancer 1. The presence of microsatellite instability (MSI-H) in colorectal cancers have a better prognosis as compared to microsatellite stable (MSS) colorectal cancer 2-5. The mechanisms that confer this benefit are not fully understood, but an association has been linked to the prominent infiltration of immune cells within the tumor 6. Increased focus on the tumor microenvironment has identified inflammatory activity as a critical predictor of disease activity impacting patient prognosis. The host immune response has been implicated in tumor behavior as it influences all phases of tumor development and growth 7-9. Tumor-infiltrating lymphocytes (TILs) in histopathological analysis of CRC is often interpreted as the host protecting against tumor development 10,11. TILs mediate re...

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

“…The good prognosis CD8a density-high/FAP intensity-high cases showed a significantly higher density of FoxP3-positive T cells ( Figure 4A). FoxP3 density has been associated with good prognosis in CRC in earlier studies [37][38][39][40][41]. The mechanisms underlying the good prognosis associations of FoxP3 T cells in CRC remain to be conclusively defined but have been suggested to include the attenuation of progression-driven inflammation.…”

<p>Combining Immunoscore with Clinicopathologic Features in Cholangiocarcinoma: An Influential Prognostic Nomogram</p>

“…For example, patients with similar clinicopathological parameters and tumor stage may have enormously different prognoses, which may be related to the interaction between the tumor and the immune response. 15,20 It has been demonstrated in various types of cancer that the immune system plays an essential role in the occurrence and progression of tumors. Innovative and…”

“…Binary scores for each immune cell type in different tumor regions are determined according to the cut-off threshold. 17,18,20 ( Figure 2). The Immunoscore for each patient was obtained by the sum of four binary score values and ranged from 0 to 4.…”

“…OncoTargets and Therapy 2020:13 11372 highly effective immunomodulatory therapies had an excellent performance in the treatment of various types of cancer, including melanoma, lung cancer, and kidney cancer. 20,32 However, data on the role of the immune system in the treatment and prognosis of patients with CCA is lacking. Comparison of the sensitivity and specificity between the Immunoscore system and the TNM staging system in predicting LRFS and OS of cholangiocarcinoma patients.…”

“…Hence, it is essential for the development of immunotherapy. [17][18][19][20] Thus far, the Immunoscore outperforms the traditional TNM staging in predicting relapse, and the survival status had been confirmed in numerous types of malignant tumors. 19,21 However, data on immune infiltration in CCA are currently scarce, and further investigation is warranted.…”