<scp>PD</scp>‐1+ <scp>TIM</scp>‐3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer

Nakano, Michitaka; Ito, Mamoru; Tanaka, Risa; Yamaguchi, Kyoko; Ariyama, Hiroshi; Mitsudo, Kenji; Yoshihiro, Tomoyasu; Ohmura, Hirofumi; Tsuruta, Nobuhiro; Hanamura, Fumiyasu; Sagara, Kosuke; Okumura, Yuta; Nio, Kenta; Tsuchihashi, Kazufumi; Arita, Shuji; Kusaba, Hitoshi; Akashi, Koichi; Baba, Eishi

doi:10.1111/cas.13723

Cited by 36 publications

(33 citation statements)

References 14 publications

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“…Nevertheless, in solid tumors, they can comprise the majority of TILs, leading to a failure in tumor regression [ 138 ]. In metastatic gastrointestinal solid tumors with ascites, including pancreatic cancer, TIM-3 co-expresses with PD-1 on TILs, which is associated with worse clinical outcomes [ 139 ]. According to Pu-Ji et al, high TIM-3 expression was significantly higher in pancreatic cancer than in healthy pancreas based on immunohistochemical analysis of patient samples.…”

Section: Inhibitory Receptorsmentioning

confidence: 99%

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Saka

Gökalp

Piyade

et al. 2020

Cancers

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T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

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Section: Inhibitory Receptorsmentioning

confidence: 99%

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Saka

Gökalp

Piyade

et al. 2020

Cancers

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“…The abscopal effect refers to tumor regression at a site distant from the primary tumor because of radiotherapy [12] and is thought to depend on the activation of the immune system [13, 14]. In addition, Nakano et al found that cells positive for the exhaustion markers PD-1 and T-cell immunoglobulin and mucin domain 3 (TIM-3) and cells co-expressing PD-1 and TIM-3 abundantly exist among malignant ascites and tumor-infiltrating lymphocytes [15]. We believe that the sensitivity of nivolumab to the tumor, even in the ascites, was elevated.…”

Section: Discussion/conclusionmentioning

confidence: 99%

A Case of Advanced Gastric Cancer with Peritoneal Metastasis Treated Successfully with Nivolumab

et al. 2019

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Peritoneal metastasis (PM) is detected in 14% of gastric cancers at the time of initial diagnosis, with a median survival time of 4 months. A 66-year-old woman diagnosed with cT4a(SE) N2M1(LYN) cStage IV was treated with three lines of chemotherapy for a year. During the third line of chemotherapy, computed tomography (CT) scan revealed a large amount of ascites, periportal collar sign, and bilateral ureteral stenosis owing to PM. The tumor biomarkers (CEA and CA 19–9) remained elevated similar to the initial levels. The patient was administered 3 mg/kg nivolumab intravenously biweekly as the fourth line of chemotherapy. Three months after the nivolumab treatment, gastroscopy revealed an extreme reduction of the tumor size, while CT scan revealed the absence of ascites and a well-controlled tumor. There was no immune-related adverse event with nivolumab during and after the treatment, and performance status improved to 0. The patient has been alive for about 2.5 years since her first visit with her sixth line of chemotherapy (docetaxel). We report a case of advanced gastric cancer with PM that was treated successfully with nivolumab.

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“…Liquid biopsy can be utilized also in other biofluids such as saliva, pleural effusions (PE), and CSF due to the content of tumor-derived genetic information, especially circulating cell-free tumor DNA (ctDNA) or other cancer-associated molecules [ 29 ]. Besides, malignant ascites as a result of peritoneal dissemination of cancer cells could be a good source of a liquid biopsy sample due to its accessibility, predominantly in gastrointestinal cancers [ 30 ]. Moreover, liquid biopsy concerning breast ductal fluid, breast milk, seminal fluid, cervical and vaginal secretions, and uterine/utero-tubular lavage can improve the management of various genital cancers of men as well as women [ 31 , 32 , 33 , 34 , 35 , 36 ].…”

Section: Liquid Biopsy Classificationmentioning

confidence: 99%

“…Pathological accumulation of fluid, which is also known as ascites, is related to various pathologies including cancer [ 185 ]. Malignant ascites contain tumor cells, fibroblasts, mesothelial cells, and inflammatory cells that produce various cytokines leading to the formation of tumor microenvironment in malignant ascites [ 30 ]. Patients with malignant ascites have poor prognosis and short overall survival [ 185 ].…”

Section: Other Liquid Biopsy Typesmentioning

confidence: 99%

“…Tumor-infiltrating lymphocytes can be useful in the prediction of prognosis and response to immune checkpoint inhibitors. Importantly, a large amount of CD4+ and CD8+ T cells demonstrate an exhausted phenotype within gastrointestinal malignant ascites, which is associated with significant clinical relevance as a prognostic and therapeutic target in advanced gastrointestinal cancer [ 30 ].…”

Section: Other Liquid Biopsy Typesmentioning

confidence: 99%

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Liquid Biopsy is Instrumental for 3PM Dimensional Solutions in Cancer Management

Líšková

Samec

Koklesová

et al. 2020

JCM

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One in every four deaths is due to cancer in Europe. In view of its increasing incidence, cancer became the leading cause of death and disease burden in Denmark, France, the Netherlands, and the UK. Without essential improvements in cancer prevention, an additional 775,000 cases of annual incidence have been prognosed until 2040. Between 1995 and 2018, the direct costs of cancer doubled from EUR 52 billion to EUR 103 billion in Europe, and per capita health spending on cancer increased by 86% from EUR 105 to EUR 195 in general, whereby Austria, Germany, Switzerland, Benelux, and France spend the most on cancer care compared to other European countries. In view of the consequent severe socio-economic burden on society, the paradigm change from a reactive to a predictive, preventive, and personalized medical approach in the overall cancer management is essential. Concepts of predictive, preventive, and personalized medicine (3PM) demonstrate a great potential to revise the above presented trends and to implement cost-effective healthcare that benefits the patient and society as a whole. At any stage, application of early and predictive diagnostics, targeted prevention, and personalization of medical services are basic pillars making 3PM particularly attractive for the patients as well as ethical and cost-effective healthcare. Optimal 3PM approach requires novel instruments such as well-designed liquid biopsy application. This review article highlights current achievements and details liquid biopsy approaches specifically in cancer management. 3PM-relevant expert recommendations are provided.

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PD‐1+ TIM‐3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer

Cited by 36 publications

References 14 publications

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

A Case of Advanced Gastric Cancer with Peritoneal Metastasis Treated Successfully with Nivolumab

Liquid Biopsy is Instrumental for 3PM Dimensional Solutions in Cancer Management

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