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      Prognostic implications of intratumoral CD103 + tumor-infiltrating lymphocytes in pulmonary squamous cell carcinoma

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          Abstract

          CD103 is the α E subunit of α Eβ 7 integrin that is expressed in tissue-resident memory T cells, where it promotes cytotoxic T cell responses against tumors. However, little is known about its expression or clinicopathological implications in non-small cell lung cancer (NSCLC). This study investigated the prognostic implications of CD103 + tumor-infiltrating lymphocytes (TILs) in NSCLC. We established two cohorts: patients with resected NSCLC ( n = 132) and patients with pulmonary squamous cell carcinoma (pSCC), a subset of NSCLC ( n = 378), to estimate the prognostic significance of CD103 + TILs. The numbers of CD103 + TILs in the intratumoral (i.e., intraepithelial) and stromal regions of NSCLC were estimated using immunohistochemistry and automated image analysis. In the NSCLC cohort, high numbers of intratumoral CD103 + TILs were significantly associated with prolonged disease-free survival (DFS) and overall survival (OS) in patients with pSCC but not in those with pulmonary adenocarcinoma. In the pSCC cohort, a positive correlation was observed between the numbers of intratumoral CD103 + and CD8 + TILs (correlation coefficient = 0.736, P < 0.001). The ratio of intratumoral/stromal CD103 + TILs was higher in pSCC with high compared to low E-cadherin expression ( P = 0.021). According to Kaplan-Meier analysis, high intratumoral but not stromal CD103 + TILs were associated with prolonged DFS and OS in patients with resected pSCC ( P = 0.021 and 0.002, respectively). Multivariate analysis revealed that a high number of intratumoral CD103 + TILs is an independent predictor of a more favorable DFS ( P = 0.021). Thus, a high number of intratumoral CD103 + TILs is a favorable prognostic indicator in patients with pSCC.

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          Most cited references 23

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          Memory T cell subsets, migration patterns, and tissue residence.

          Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4(+) and CD8(+) T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.
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            The tumour microenvironment as a target for chemoprevention.

            New data indicate that primary dysfunction in the tumour microenvironment, in addition to epithelial dysfunction, can be crucial for carcinogenesis. These recent findings make a compelling case for targeting the microenvironment for cancer chemoprevention. We review new insights into the pathophysiology of the microenvironment and new approaches to control it with chemopreventive agents. The microenvironment of a cancer is an integral part of its anatomy and physiology, and functionally, one cannot totally dissociate this microenvironment from what have traditionally been called 'cancer cells'. Finally, we make suggestions for more effective clinical implementation of this knowledge in preventive strategies.
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              Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer.

              The presence of CD8(+) tumor-infiltrating lymphocytes (TIL) is associated with prolonged survival in high-grade serous ovarian cancer (HGSC) and other epithelial cancers. Survival is most strongly associated with intraepithelial versus intrastromal CD8(+) TILs; however, the mechanisms that promote the intraepithelial localization of TILs remain poorly understood. We hypothesized that intraepithelial CD8(+) TILs, like normal mucosal intraepithelial lymphocytes, might express CD103, a subunit of αE/β7 integrin, which binds E-cadherin on epithelial cells. A large collection of primary ovarian tumors (HGSC, endometrioid, mucinous, and clear cell) was analyzed by immunohistochemistry for the presence of TIL-expressing CD103. The activation and differentiation status of CD103(+) TILs were assessed by flow cytometry. The prognostic significance of TIL subsets was evaluated by Kaplan-Meier analysis. CD103(+) TILs were present in all major ovarian cancer subtypes and were most abundant in HGSC. CD103(+) TILs were preferentially localized to epithelial regions of tumors and were comprised predominantly of CD8(+) T cells expressing activation (HLA-DR, Ki-67, PD-1) and cytolytic (TIA-1) markers, as well as CD56(+) NK cells. Tumor infiltration by CD103(+) TILs was strongly associated with patient survival in HGSC. Tumors containing CD8(+) TILs that were CD103(-) showed poor prognosis equivalent to tumors lacking CD8(+) TILs altogether. CD103(+) TILs comprise intraepithelial, activated CD8(+) T cells, and NK cells and are strongly associated with patient survival in HGSC. CD103 may serve as a useful marker for enriching the most beneficial subsets of TILs for immunotherapy. ©2013 AACR.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                21 February 2017
                10 January 2017
                : 8
                : 8
                : 13762-13769
                Affiliations
                1 Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
                2 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
                3 Department of Forensic Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
                4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
                5 Tumor Immunity Medical Research Center, Tumor Microenvironment Global Core Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea
                6 Ischemic/Hypoxia Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
                Author notes
                Correspondence to: Doo Hyun Chung, doohyun@ 123456snu.ac.kr
                Article
                14632
                10.18632/oncotarget.14632
                5355136
                28099920
                Copyright: © 2017 Koh et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Research Paper

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