Understanding and improving cellular immunotherapies against cancer: From cell-manufacturing to tumor-immune models

Ringquist, Rachel; Ghoshal, Delta; Jain, Ritika; Roy, Krishnendu

doi:10.1016/j.addr.2021.114003

Cited by 24 publications

(18 citation statements)

References 361 publications

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“…A deteriorating TME accompanies the increased expression of transcription factors to regulate metabolism, proliferation, and inflammation [ 36 ]. Recently, treatment with the recombinant human MG53 (TRIM72) could inhibit lung cancer tumor growth by blocking ATO-induced SG formation, suggesting that TRIM72 is a key mediator of cancer cells exposed to adverse environments [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA

Wang

et al. 2022

Anti-Cancer Drugs

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A hypoxic tumor microenvironment (TME) promotes cancer progression, yet its value as a therapeutic target remains underexploited. Tripartite motif-containing 72 (TRIM72) may protect cells against various stresses including hypoxia. Recently, low TRIM72 expression has been implicated in cancer progression. However, the biological role and molecular mechanism of TRIM72 in breast cancer (BC) remain unclear. Herein, we analyzed the TRIM72 expression in BC tissue and cell lines by western blot (WB) and quantitative reverse transcription-PCR. We established the overexpression of TRIM72 using plasmids and lentiviral-mediated upregulation, as well as downregulation of protein phosphatase 3 catalytic subunit alpha (PPP3CA) by siRNA. The tumor-suppressive roles of TRIM72 were assessed on BT549 and MDA-MB-231 cells by MTS, Transwell, and flow cytometry assays in vitro and in xenografted tumors in vivo . The molecular mechanism of TRIM72 was investigated by luciferase reporter and co-immunoprecipitation (Co-IP) assay. Lactate production was measured by ELISA under hypoxic environments induced by CoCl 2 . Moreover, the expression of PI3K/Akt/mTOR pathway-associated proteins was detected by WB in BC cells. Results showed that TRIM72 was downregulated in BC. Overexpression of TRIM72 inhibited tumor proliferation and invasion in vitro and in a xenograft tumor model. Mechanistically, PPP3CA altered the inhibitory effects of TRIM72 on hypoxia-induced lactate production and monocarboxylate transporter 4-promoter activity, as well as the effect of the PI3K/Akt/mTOR signaling pathway. Our study suggests that TRIM72 modulates the TME and plays tumor-suppressive roles in BC progression. Therefore, TRIM72 may serve as a potential therapeutic target in BC.

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Section: Discussionmentioning

confidence: 99%

TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA

Wang

et al. 2022

Anti-Cancer Drugs

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“…This hybrid fusion confers enhanced tumorigenic potential and growth advantage to the tumor cells, tissue metastasis and immune privileges due to the macrophage identity [ 300 ]. Moreover, physical conditions within the tumor such as ECM stiffness, low pH, and additional factors such as hypoxia and high interstitial fluid pressure also tend to suppress the recruitment and function of anti-tumoral immune cells [ 301 , 302 ].…”

Section: Imbalance Of Liver Immune Microenvironment and Liver Diseasesmentioning

confidence: 99%

Mesenchymal stem cells-based therapy in liver diseases

Han

Jin

2022

Mol Biomed

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Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.

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“…Immunotherapies represent one of the current most promising challenges in cancer treatment. These are based on the concept of boosting the host’s immune system toward the elimination of cancer and include several strategies such as the use of monoclonal antibodies (mAb) targeting tumor-associated molecules or blocking immune checkpoints, anti-cancer vaccines and cell-based therapies ( Ringquist et al, 2021 ; Shelton et al, 2021 ). The success of immunotherapeutic approaches aimed to unleash the activity of cytotoxic cells such as CD8 + T lymphocytes or Natural Killer (NK) cells strictly depends on their interaction with cancer cells and other immune cells.…”

Section: Introductionmentioning

confidence: 99%

“…Such interaction might be profoundly affected by the highly complex niche of the tumor microenvironment (TME), which is populated by different type of cells (i.e., stromal cells, tumor cells, immune cells), interconnected within a complex three-dimensional vascularized matrix. Given these premises, the development of reliable preclinical human models has become crucial for the assessment of the best immune therapeutic approaches ( Boucherit et al, 2020 ; Ando et al, 2021 ; Ringquist et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A multi-organ-on-chip to recapitulate the infiltration and the cytotoxic activity of circulating NK cells in 3D matrix-based tumor model

Marzagalli¹,

Pelizzoni

Fedi

et al. 2022

Front. Bioeng. Biotechnol.

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The success of immunotherapeutic approaches strictly depends on the immune cells interaction with cancer cells. While conventional in vitro cell cultures under-represent the complexity and dynamic crosstalk of the tumor microenvironment, animal models do not allow deciphering the anti-tumor activity of the human immune system. Therefore, the development of reliable and predictive preclinical models has become crucial for the screening of immune-therapeutic approaches. We here present an organ-on-chip organ on chips (OOC)-based approach for recapitulating the immune cell Natural Killer (NK) migration under physiological fluid flow, infiltration within a 3D tumor matrix, and activation against neuroblastoma cancer cells in a humanized, fluid-dynamic environment. Circulating NK cells actively initiate a spontaneous “extravasation” process toward the physically separated tumor niche, retaining their ability to interact with matrix-embedded tumor cells, and to display a cytotoxic effect (tumor cell apoptosis). Since NK cells infiltration and phenotype is correlated with prognosis and response to immunotherapy, their phenotype is also investigated: most importantly, a clear decrease in CD16-positive NK cells within the migrated and infiltrated population is observed. The proposed immune-tumor OOC-based model represents a promising approach for faithfully recapitulating the human pathology and efficiently employing the immunotherapies testing, eventually in a personalized perspective. An immune-organ on chip to recapitulate the tumor-mediated infiltration of circulating immune cells within 3D tumor model.

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Understanding and improving cellular immunotherapies against cancer: From cell-manufacturing to tumor-immune models

Cited by 24 publications

References 361 publications

TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA

TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA

Mesenchymal stem cells-based therapy in liver diseases

A multi-organ-on-chip to recapitulate the infiltration and the cytotoxic activity of circulating NK cells in 3D matrix-based tumor model

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