The key role of calreticulin in immunomodulation induced by chemotherapeutic agents

Yamamura, Yoshiyuki; Tsuchikawa, Takahiro; Miyauchi, Kengo; Takeuchi, Shintaro; Wada, Masataka; Kuwatani, Toshihiko; Kyogoku, Noriaki; Kuroda, Aki; Maki, Takehiro; Shichinohe, Toshiaki; Hirano, Satoshi

doi:10.1007/s10147-014-0719-x

Cited by 26 publications

(18 citation statements)

References 21 publications

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“…(2.3%) of B16 melanoma cell line (Yamamura et al 2015). If we tried to mimic human tumour properties and slightly increase the fraction of tumour cells expressing MHC class I, e.g.…”

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confidence: 98%

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

et al. 2019

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Cancer immunotherapy is a rapidly developing field, with numerous drugs and 15 therapy combinations waiting to be tested in pre-clinical and clinical settings. However, the costly and time-consuming trial-and-error approach to development of new treatment paradigms creates a research bottleneck, motivating the development of complementary approaches. Computational modelling is a compelling candidate for this task, however, difficulties associated with the validation of such models limits their use in pre-clinical 20 and clinical settings. Here we propose a bottom-up deterministic computational model to simulate tumour response to treatment with anti-programmed-death-1 antibodies (anti-PD-1). The model was built with validation in mind, and so contains minimum number of parameters, and only 4 free parameters. Moreover, all model parameters can be measured experimentally. Free parameters were tuned by fitting the model to 25 experimental data from the literature, using B16-F10 murine melanoma implanted into wild type (C57BL/6), as well as into immunodeficient (NSG) mice strains, and treated with anti-PD-1 antibodies. The model's predictive ability was verified on two independent datasets from literature with different but well-known inputs. To identify possible biomarkers of response to anti-PD-1 immunotherapy, sensitivity study of key model 30 parameters was performed. Good agreement between the simulated tumour growth curves and the experimental data was achieved, with mean relative deviations in the range of 13

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“…(2.3%) of B16 melanoma cell line (Yamamura et al 2015). If we tried to mimic human tumour properties and slightly increase the fraction of tumour cells expressing MHC class I, e.g.…”

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confidence: 98%

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

et al. 2019

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“…Calreticulin is a 46–65‐kDa chaperone protein located in the ER that has diverse roles in cellular metabolism, including Ca 2+ homeostasis, cell adhesion, and HLA class I assembly. Recent studies indicate that chemotherapeutic agents such as mitoxantrone and oxaliplatin trigger CRT translocation from the ER to the cell surface, resulting in induced anticancer immune response; it has also been suggested that anti‐CRT antibodies can be used for the early diagnosis of pancreatic cancer . However, CRT overexpression has been associated with the development and progression of pancreatic cancer .…”

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confidence: 99%

Calreticulin is highly expressed in pancreatic cancer stem‐like cells

et al. 2016

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Cancer stem‐like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P‐CSLCs). A P‐CSLC‐enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by 2‐D electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P‐CSLCs compared to parental cells. Flow cytometry analysis indicated that CRT was mostly localized to the surface of P‐CSLCs and did not correlate with the levels of CD44v9, another P‐CSLC biomarker. Furthermore, the side population in the CRThigh/CD44v9low population was much higher than that in the CRTlow/CD44v9high population. Calreticulin expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and postoperative therapy. Our results suggest that CRT can serve as a biomarker of P‐CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.

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“…Although some chemotherapeutic agents can induce tumor-specific immune responses (e.g., mitoxantrone, 5-FU, camptothecin, and cisplatin; ref. 40), mainly through the induction of immunogenic Higher doses of Antartina exerted a more potent antitumor effect against CT26 colorectal carcinoma tumors in vivo. A, BALB/c mice were subcutaneously injected with 5 Â 10 5 CT26 cells into the right flank (day 0), and tumors reach approximately 90 mm 3 before treatment was started.…”

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confidence: 99%

A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response

Malvicini

Gutiérrez-Moraga

Rodríguez

et al. 2018

Molecular Cancer Therapeutics

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In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits human colorectal carcinoma cell proliferation; however, experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in>30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. .

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The key role of calreticulin in immunomodulation induced by chemotherapeutic agents

Abstract: In conclusion, chemotherapeutic drugs can improve the immunogenicity of cancer cells in a cell-specific manner through the mechanism of translocation of CRT.

Cited by 26 publications

References 21 publications

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

Calreticulin is highly expressed in pancreatic cancer stem‐like cells

A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response

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