Microfluidic technologies for immunotherapy studies on solid tumours

Paterson, Karla; Zanivan, Sara; Glasspool, Ros; Coffelt, Seth B.; Zagnoni, Michele

doi:10.1039/d0lc01305f

Cited by 24 publications

(14 citation statements)

References 97 publications

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“…Despite epacadostat-induced lymphocyte migration, we did not observe a significant difference in apoptotic percentage or in proliferation rate of HSC-3 cells, which suggests a more complex underlying mechanism. In general, the ratio of cancer cells to leukocytes in the in vitro experiments ranged from 1:5 to 1:10, thus giving the leukocytes an advantage ( 13 , 25 , 26 ). In our experiment, we set the cancer cell-lymphocyte ratio at 1:100.…”

Section: Discussionmentioning

confidence: 99%

“…Although this was not ideal, obtaining sufficient lymphocytes and cancer cells from the same patient is not feasible. Therefore, methodologies similar to ours, where leukocytes are isolated from healthy individuals, have commonly been used in the literature ( 25 , 26 , 51 ). As our results show variable effects depending on ICI on OSCC cell migration and apoptosis and on lymphocyte cytokine secretion, further in vivo experiments are warranted to validate these findings.…”

Section: Discussionmentioning

confidence: 99%

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IDO1 Inhibition Reduces Immune Cell Exclusion Through Inducing Cell Migration While PD-1 Blockage Increases IL-6 and -8 Secretion From T Cells in Head and Neck Cancer

et al. 2022

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BackgroundImmune checkpoint inhibitors (ICIs), primarily anti-PD-1, are currently used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients benefit from these costly therapies. Therefore, there is an unmet need to better understand the effect of ICIs on immune effector cells. This study aimed to investigate the effect of a PD-1 antibody and an IDO1 inhibitor on different lymphocyte populations (NK, CD4+, and CD8+ T cells) in term of migration, cytotoxicity, and cytokine release in the presence of HNSCC cells.MethodsUsing a microfluidic chip, we injected HSC-3 cells (an oral tongue squamous cell carcinoma cell line) embedded in a human tumor-derived matrix “myogel/fibrin” together with NK, CD4+, and CD8+ T cells in separate channels. The two channels were connected with microchannels. The PD-1 antibody nivolumab and IDO1 inhibitor epacadostat were added to the microfluidic chips. Lymphocyte migration and cytotoxicity were examined under fluorescent microscopy and cytokine release was measured using a FirePlex Human Discovery Cytokines Immunoassay.ResultsEpacadostat significantly increased the migration and infiltration of NK and CD4+ T cells, but not CD8+ T cells, towards the cancer cells. Nivolumab did not exhibit a similar effect. While CD8+ T cells alone showed near to no migration, adding CD4+ T cells enhanced migration towards the cancer cells. There was a mild nonsignificant increase in apoptosis of HSC-3 cells after adding epacadostat to lymphocytes. In contrast, HSC-3 proliferation was not affected by lymphocytes regardless of ICIs. Nivolumab significantly increased release of MIP1-α, IL-6, and IL-8 from NK, CD4+, and CD8+ T cells, respectively.ConclusionsThis study revealed that each subpopulation of lymphocytes respond differently to ICIs. We also revealed the subpopulation of lymphocytes responsible for the increases in specific serum cytokines after ICI treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IDO1 Inhibition Reduces Immune Cell Exclusion Through Inducing Cell Migration While PD-1 Blockage Increases IL-6 and -8 Secretion From T Cells in Head and Neck Cancer

et al. 2022

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“…Miniaturized 3D immunoassays have been developed using microfluidic and lab-on-a-chip technology, [20][21][22][23][24][25][26][27][28][29] yet their application is still limited in relation to CAR-T studies. [30] For example, Ando et al established a microfluidic assay to study the effect of hypoxic conditions on CAR-T cell behaviour. [31] Pavesi et al studied T cell efficacy in an inflammatory and hypoxic microenvironment where 2D assays showed significantly greater killing by T cells in comparison to 3D microfluidic studies, emphasizing the importance of 3D models during in vitro modelling.…”

Section: Himericmentioning

confidence: 99%

“…[32] Therefore, miniaturized technology platforms facilitating screening of preclinical models that better mimic the Assessment of CAR-T cell-mediated cytotoxicity in 3D microfluidic cancer coculture models for combination therapy K. In this paper, we have developed a novel proof-of-concept microfluidic immunoassay to assess CAR-T cell-mediated cytotoxicity and off-target identification on multiple triplenegative breast cancer (TNBC) -stroma co-culture spheroids, using high EGFR expressing cancer cells and low EGFR expressing normal fibroblasts or CAFs, largely neglected in in vitro CAR-T models [33] and implicated in the outcomes of many therapies. [8,30,34]. A TNBC model was chosen as TNBC makes up to 20% of breast cancer cases, is highly aggressive and lacks successful therapeutic options.…”

Section: Himericmentioning

confidence: 99%

Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy

Paterson

Paterson²,

Mulholland³

et al. 2022

IEEE Open J. Eng. Med. Biol.

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Chimeric antigen receptor (CAR)-T cell therapy is efficacious against many haematological malignancies, but challenges remain when using this cellular immunotherapy for treating solid tumours. Classical 2D in vitro models fail to recapitulate the complexity of the tumour microenvironment, whilst in vivo models, such as patient-derived xenografts, are costly and labour intensive. Microfluidic technologies can provide miniaturized solutions to assess CAR-T therapies in 3D complex preclinical models of solid tumours. Here, we present a novel microfluidic immunoassay for the evaluation of CAR-T cell cytotoxicity and targeting specificity on 3D spheroids containing cancer cells and stromal cells. Monitoring the interaction between CAR-T cells and spheroid co-cultures, we show that CAR-T cells home towards target-expressing cancer cells and elicit a cytotoxic effect. Testing CAR-T cells in combination therapies, we show that CAR-T cell cytotoxicity is enhanced with anti-PD-L1 therapy and carboplatin chemotherapy. We propose this proof-of-concept microfluidic immunoassay as a materialsaving, pre-clinical screening tool for quantification of cell therapy efficacy. Index Terms -Immunotherapy, Lab-on-a-chip, Solid Tumour Microenvironment, Three-dimensional in vitro complex model. Impact Statement-Microfluidic platforms and protocols canprovide powerful, cost-effective and miniaturised in vitro assays to preclinically assess CAR-T cell therapies in solid tumours.

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“…Anti-cancer vaccines have also been under investigation using microfluidic platforms, such as the CellSqueeze commercial system, incorporating microchannels to squeeze and stretch cells for permitting rapid vaccine delivery [254,255]. Finally, anti-cancer virotherapy investigations have utilized microfluidic devices to monitor oncolytic viruses in real time, study bystander infection, and localize viruses according to the pH level [256][257][258][259][260].…”

Section: Drug Development and Deliverymentioning

confidence: 99%

Application of Microfluidic Systems for Breast Cancer Research

et al. 2022

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Cancer is a disease in which cells in the body grow out of control; breast cancer is the most common cancer in women in the United States. Due to early screening and advancements in therapeutic interventions, deaths from breast cancer have declined over time, although breast cancer remains the second leading cause of cancer death among women. Most deaths are due to metastasis, as cancer cells from the primary tumor in the breast form secondary tumors in remote sites in distant organs. Over many years, the basic biological mechanisms of breast cancer initiation and progression, as well as the subsequent metastatic cascade, have been studied using cell cultures and animal models. These models, although extremely useful for delineating cellular mechanisms, are poor predictors of physiological responses, primarily due to lack of proper microenvironments. In the last decade, microfluidics has emerged as a technology that could lead to a paradigm shift in breast cancer research. With the introduction of the organ-on-a-chip concept, microfluidic-based systems have been developed to reconstitute the dominant functions of several organs. These systems enable the construction of 3D cellular co-cultures mimicking in vivo tissue-level microenvironments, including that of breast cancer. Several reviews have been presented focusing on breast cancer formation, growth and metastasis, including invasion, intravasation, and extravasation. In this review, realizing that breast cancer can recur decades following post-treatment disease-free survival, we expand the discussion to account for microfluidic applications in the important areas of breast cancer detection, dormancy, and therapeutic development. It appears that, in the future, the role of microfluidics will only increase in the effort to eradicate breast cancer.

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Microfluidic technologies for immunotherapy studies on solid tumours

Abstract: Immunotherapy is a powerful and targeted cancer treatment that exploits the body's immune system to attack and eliminate cancerous cells.

Cited by 24 publications

References 97 publications

IDO1 Inhibition Reduces Immune Cell Exclusion Through Inducing Cell Migration While PD-1 Blockage Increases IL-6 and -8 Secretion From T Cells in Head and Neck Cancer

IDO1 Inhibition Reduces Immune Cell Exclusion Through Inducing Cell Migration While PD-1 Blockage Increases IL-6 and -8 Secretion From T Cells in Head and Neck Cancer

Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy

Application of Microfluidic Systems for Breast Cancer Research

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