The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

Chu, Grace; Zandwijk, Nico van; Rasko, John E.J.

doi:10.3389/fonc.2019.01366

Cited by 56 publications

(71 citation statements)

References 123 publications

(220 reference statements)

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“…However, when installed, mesotheliomas develop a stong suppressive local immune microenvironment [37]. This correlates with impaired functional activity of NK cells [32,36], suggesting that this tumor microenvironment inhibits their protective effect.…”

Section: Discussionmentioning

confidence: 99%

Lactate dehydrogenase-elevating virus enhances natural killer cell-mediated immunosurveillance of mouse mesothelioma development

Mandour¹,

Soe²,

Uyttenhove³

et al. 2020

Infect Agents Cancer

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Background: Viral infections can reduce early cancer development through enhancement of cancer immunosurveillance. This study was performed to analyse this effect of viral infection in a mouse model of solid tumor. Methods: The experimental model used was the effect of BALB/c mouse infection by lactate dehydrogenaseelevating virus on AB1 mesothelioma cancer development. Results: Acute infection with lactate dehydrogenase-elevating virus strongly reduced in vivo early AB1 mesothelioma growth and death resulting from cancer development. This effect was not due to a direct cytolytic effect of the virus on AB1 cells, but to an in vivo activation of natural killer cells. Gamma-interferon production rather than cytotoxic activity against AB1 cells mediated this protective effect. This gamma-interferon production by natural killer cells was dependent on interleukin-12 production. Conclusions: Together with other reported effects of infectious agents on cancer development, this observation may support the hypothesis that enhancement of innate immunosurveillance against tumors may result from infection with common infectious agents through modulation of the host immune microenvironment.

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Section: Discussionmentioning

confidence: 99%

Lactate dehydrogenase-elevating virus enhances natural killer cell-mediated immunosurveillance of mouse mesothelioma development

Mandour¹,

Soe²,

Uyttenhove³

et al. 2020

Infect Agents Cancer

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“…Even the presence of regulatory T cells or CTLA-4 cells may not actually be able to fight back mesothelioma once they are inside the tumor. Chu [14] discusses many ways in which mesothelioma is able to resist the body's immune response. Therefore, two additional scenarios regarding the effects of chemotherapy on the immune response are investigated:…”

Section: Realistic Treatment Timelinesmentioning

confidence: 99%

“…Mesothelioma is aggressive due to its ability to evade and inactivate the immune system [14]. Despite the infiltration of immune cells into the tumor microenvironment to compete for oxygen and key nutrients, mesothelioma cells can substantially affect T-cell function by releasing Glucose Transporter 1 to more efficiently access glucose.…”

mentioning

confidence: 99%

“…Chu et. al [14] describe many additional pathways in which mesothelioma can successfully hinder the immune response, providing a rationale for the general ineffectiveness of immunotherapy in its treatment [43]. On the other hand, addition of bevacizumab to pemetrexed plus cisplatin significantly improved overall survival in mesothelioma with tolerable toxicity [62] and is now the standard treatment for the disease [23].…”

mentioning

confidence: 99%

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Combined therapy for treating solid tumors with chemotherapy and angiogenic inhibitors

Glick¹,

Mastroberardino²

2020

DCDS-B

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Anti-angiogenesis therapy has been an emerging cancer treatment which may be further combined with chemotherapy to enhance overall survival of cancer patients. In this paper, we investigate a system of nonlinear ordinary differential equations describing a microenvironment consisting of host cells, tumor cells, immune cells and endothelial cells while incorporating treatment combination with chemotherapy and anti-angiogenesis therapy. We perform a dynamical systems analysis demonstrating that our model is able to capture the three phases of cancer immunoediting: elimination, equilibrium, and escape. In addition, we present transcritical bifurcations for relevant parameter values that correspond to the progression from the elimination phase to the equilibrium phase. A range of medically useful tumor doubling times were simulated to determine how combined therapy affects the tumor microenvironment over the course of a 250 day treatment. This analysis found two additional bifurcation parameters that move the system of equations from the equilibrium phase to the elimination phase. We determine that the most important aspect of an effective therapy is the activation of the anti-tumor immune response.

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“…Upon binding to their ligands (e.g. programmed cell death ligand, PD-L1), these molecules mediate an exhausted phenotype and apoptosis, thus limiting T cell anti-tumor activity [28,29]. Following the success of a phase III trial using CI showing a 4-month survival gain [30], the FDA has recently approved the Nivolumab (against PD-1) and Ipilimumab (against CTLA-4) combination for unresectable MM.…”

Section: Introductionmentioning

confidence: 99%

Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

et al. 2021

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Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

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The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

Cited by 56 publications

References 123 publications

Lactate dehydrogenase-elevating virus enhances natural killer cell-mediated immunosurveillance of mouse mesothelioma development

Lactate dehydrogenase-elevating virus enhances natural killer cell-mediated immunosurveillance of mouse mesothelioma development

Combined therapy for treating solid tumors with chemotherapy and angiogenic inhibitors

Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

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