Prognostic significance of resident CD103+CD8+T cells in human colorectal cancer tissues
Introduction
Colorectal cancer is a major type of cancer from digestive tract worldwide (Bray et al., 2018; Chen et al., 2016; Siegel et al., 2018). In recent decades, the prevalent application of endoscopy screening significantly improves the early detection and helps the diagnosis as well as the treatment for the patients (Antonelli et al., 2018; Lopez et al., 2019). However, the overall survival (OS) of the patients with advanced stages still remains poor. In addition to the chemotherapy, target therapy, radiotherapy, or even combined therapeutic strategies, the immunotherapy including immune checkpoint blockade therapy (ICBT) and adoptive immune cell therapy, has shown great improvement for the clinical outcome of the refractory cases (Topalian et al., 2012). Moreover, the tumor microenvironment can be classified into “hot” or “cold” based on the influx level of multiple immune cells and cytokines (Kim et al., 2018; LaRocca and Warner, 2018; Sharma et al., 2017). And the patients with “hot” tumor usually are usually more responsive to ICBT and would benefit from immunotherapy (Ribas et al., 2017).
We have previously demonstrated that the intensity of tumor infiltrating T cells (TILs) in human cancers tissues is significantly correlated with cancer progression and post-operative prognosis of the patients (Chen et al., 2015, 2011; Chen et al., 2013; Lu et al., 2011; Xu et al., 2017; Zheng et al., 2017). Among all these TILs, the CD8+T cells can serve as one of the most important populations of T cells mediating anti-tumor response (Chen et al., 2013; Lu et al., 2011; Wang et al., 2015). Therefore, numerous studies have unveiled that the numbers, the sub-population and the functions of these tumor infiltrating CD8+T cells in cancer tissues decisively affect the tumor outcomes (Cho et al., 2003). We have previously shown that T-bet is highly expressed in tumor infiltrating CD8+T cells in human gastric cancers and ovarian cancers, indicating that the T-bet+CD8+T cell sub-population is an important prognostic predictor for the prognosis of the patients (Chen et al., 2013; Xu et al., 2017). Therefore, it’s absolutely necessary to further identify more effective factors by using well-defined CD8+T cell sub-populations to assist the clinical evaluation of the cancer patients.
Recently, it’s of note that the resident T cells in tumor tissues have been accepted as a prevalent tumor-reactive T cells population in T-cell-mediated anti-tumor response (Sarrabayrouse et al., 2011). CD103, the receptor of E-cadherin, can be widely expressed on lymphoid cells those localized in epithelial tissues, and thus it is considered as the pivotal marker for tissue resident lymphoid cells (Fan and Rudensky, 2016). The interaction between CD103 and E-cadherin can not only lead to the residence of CD8+T cells in tumor tissues, but also could trigger the activation of resident CD8+T and the release of Perforin and Granzyme B from these cells, finally resulting in enhanced anti-tumor immune response (Franciszkiewicz et al., 2009; Le Floc’h et al., 2007). As of now, many studies have shown that increased numbers of resident CD8+T cells in human cancer tissues are significantly correlated with a better OS and prevented cancer progression in human lung cancer and ovarian cancer (Djenidi et al., 2015; Enamorado et al., 2017; Koh et al., 2017; Webb et al., 2014). It is worth mentioning that high levels of CD103 expression in tumor infiltrating CD8+T cells represent increased cytotoxicity (Ganesan et al., 2017).
In our present study, we aimed to characterize the resident CD8+T cells in human colorectal cancer tissues by using double staining of CD103 and CD8, and further evaluated the prognostic significance and clinical implications of the intensity of resident CD8+T cells. Collectively, our data demonstrated that in colorectal cancer tissues, the increased numbers of resident CD103+CD8+T cells in cancer tissues were significantly correlated with a better OS of the patients and therefore could be used as an important prognostic predictor for this malignancy.
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Patients and tissue samples
Tissue micro-arrays including human colon cancer (HColA180Su14) and human rectum cancer (HRec-Ade180Sur-03) were purchased from Shanghai Outdo Biotech Co., Ltd. (Shanghai, China). All the survival data of the patients were available. The detailed clinic pathological parameters of all the patients were shown in the Table 1, Table 2, Table 3 in this report. The tumor-node-metastasis (TNM) stages were assigned according to the American Joint Committee on cancer criteria. This study was approved by
Survey of prognostic values of CD8 and CD103 expression at the mRNA level in human colorectal cancer tissues based on TCGA data
Based on the TCGA data from http://gepia.cancer-pku.cn/, we first studied the prognostic value of both CD8 and CD103 expressions at the mRNA level. As shown in Fig. 1A and B, we found that the OS and the DFS (disease free survival, DFS) of the colorectal cancer patients with higher mRNA level of CD8 in cancer tissues trends to be better than those of the patients with lower CD8 (OS: P = 0.24, DFS: P = 0.096). Fig. 1C illustrates that the OS of the colorectal cancer patients with higher mRNA
Discussion
We have previously reported that the intensity of tumor infiltrating T cells, especially CD8+T cells, can serve as an important prognostic predictor for the patients suffering from digestive tract cancers (Chen et al., 2015, 2011; Lu et al., 2011). Moreover, T-bet, an essential control and an important functional modulator of type I immune response, has been shown to be highly expressed in tumor infiltrating CD8+T cells (Chen et al., 2013; Xu et al., 2017). In the present study, we focused on
Conflicts of interest
The authors disclose no potential conflicts of interest.
CRediT authorship contribution statement
Wenwei Hu: Data curation, Writing - original draft, Software, Validation. Runzi Sun: Visualization, Investigation, Software, Validation. Lujun Chen: Data curation, Writing - original draft, Writing - review & editing. Xiao Zheng: Software, Validation. Jingting Jiang: Conceptualization, Methodology, Software, Supervision, Writing - review & editing.
Acknowledgements
This work was supported by grants from the National Key R&D Program (2018YFC1313400), the National Science and Technology Support Project (2015BAI12B12), the National Natural Science Foundation of China (81301960, 31570877, 31570908), the Key R&D Project of Science and Technology Department of Jiangsu Province (BE2018645, BE2015633), Changzhou High-Level Medical Talents Training Project (No. 2016CZBJ001), and Changzhou Science and Technology Project (No. CJ20160021, CE20165051).
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These authors contributed equally to this work.