LIGHT Delivery to Tumors by Mesenchymal Stem Cells Mobilizes an Effective Antitumor Immune Response

Zou, Weibin; Zheng, Huilin; He, Tong Chuan; Chang, Jinjia; Fu, Yang–Xin; Fan, Weimin

doi:10.1158/0008-5472.can-11-4216

Cited by 44 publications

(32 citation statements)

References 53 publications

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“…In vitro and in vivo MSCs migration assays were performed as previously reported (20). In brief, 5 Â 10 5 MSCs were incubated in serum-free medium for 48 hours and the resulting conditioned media were used as chemoattractants.…”

Section: In Vitro and In Vivo Msc Migration Assaymentioning

confidence: 99%

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice

Wei

Chen

Lu³

et al. 2014

Molecular Cancer Therapeutics

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Mesenchymal stem cells (MSC) represent a new tool for delivery of therapeutic agents to cancer sites because of their strong tropism toward tumors. IL15 has demonstrated a potent antitumor activity in various animal models as well as clinical trials. However, because of its short half-life, effective therapeutic effects usually require a high dose, which often results in undesired side effects; thus, new strategies for overcoming this disadvantage are needed. In this study, human MSCs were isolated from umbilical cord blood as delivery vehicles and transduced with lentivirus vector expressing murine IL15 (MSC-IL15). In vitro assays of lymphocyte activation and proliferation demonstrated that IL15 produced by MSCs was biofunctional. In syngeneic mice bearing Pan02 pancreatic tumors, systemic administration of MSC-IL15 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice, which were associated with tumor cell apoptosis, and natural killer (NK)-and T-cell accumulation. Furthermore, we confirmed that MSC-IL15 could migrate toward tumor and secreted IL15 in tumor-specific sites. Depletion of NK and CD8 þ T cells abolished the antitumor activity of MSC-IL15, suggesting that NK and CD8 þ T cells play a key role for MSC-IL15-mediated effect. Interestingly, cured mice after MSC-IL15 treatment were resistant to Pan02 pancreatic tumor rechallenge, and adoptive transfer of lymphocytes from cured mice also could cause rejection of Pan02 tumor inoculation in na€ ve mice, indicating that MSC-IL15 induced tumor-specific T-cell immune memory response. Overall, these data support that MSCs producing IL15 might represent an innovative strategy for therapy of pancreatic tumor.

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Section: In Vitro and In Vivo Msc Migration Assaymentioning

confidence: 99%

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice

Wei

Chen

Lu³

et al. 2014

Molecular Cancer Therapeutics

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“…50 Furthermore, several studies have demonstrated MSC tropism on tumors, and our recent work also proved that MSCs can recruit macrophages and promote tumor growth. 24,51,52 Emerging evidence supports the idea that induction of mutations in stromal cells can promote tumor formation. Genetic mutations in stromal cells have been reported in breast cancer.…”

Section: Discussionmentioning

confidence: 90%

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

Huang

et al. 2013

Oncogene

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p53 is one of the most studied genes in cancer biology, and mutations in this gene may be predictive for the development of many types of cancer in humans and in animals. However, whether p53 mutations in non-tumor stromal cells can affect tumor development has received very little attention. In this study, we show that B16F0 melanoma cells form much larger tumors in p53-deficient mice than in wild-type mice, indicating a potential role of p53 deficiency in non-tumor cells of the microenvironment. As mesenchymal stem cells (MSCs) are attracted to tumors and form a major component of the tumor microenvironment, we examined the potential role of p53 status in MSCs in tumor development. We found that larger tumors resulted when B16F0 melanoma cells were co-injected with bone marrow MSCs derived from p53-deficient mice rather than MSCs from wild-type mice. Interestingly, this tumor-promoting effect by p53-deficient MSCs was not observed in non-obese diabetic/severe combined immunodeficiency mice, indicating the immune response has a critical role. Indeed, in the presence of inflammatory cytokines, p53-deficient MSCs expressed more inducible nitric oxide synthase (iNOS) and exhibited greater immunosuppressive capacity. Importantly, tumor promotion by p53-deficient MSCs was abolished by administration of S-methylisothiourea, an iNOS inhibitor. Therefore, our data demonstrate that p53 status in tumor stromal cells has a key role in tumor development by modulating immune responses.

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“…These include modification to produce immunostimulatory cytokines (e.g. IFN-α, IFN-β, IL-12) and T cell trafficking molecules such as LIGHT [50][51][52][53].…”

Section: Strategies To Counteract Adaptive Resistance To Immune Checkmentioning

confidence: 99%

Immune Checkpoint Blockade and Adaptive Immune Resistance in Cancer

Wong¹,

Cameron²

2017

Immunotherapy - Myths, Reality, Ideas, Future

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The clinical success of immune checkpoint blockers is a pivotal advancement for treating an increasing number of cancer types. However, immune checkpoint blockers still rarely induce complete remission and show little to no therapeutic efficacy in a significant percentage of cancer patients. Efforts are now underway to identify biomarkers that accurately predict which patients benefit from immune checkpoint blockers. Moreover, adaptive immune resistance can develop in tumors during treatment with immune checkpoint blockers. These adaptive resistance mechanisms in tumors might be disrupted by combining adjunctive immunotherapies, which could potentially improve the therapeutic efficacy of immune checkpoint blockers. This chapter discusses the mechanism of action of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1/ programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint blockers and biomarkers that might predict clinical responses to these drugs. Lastly, ongoing research on mechanisms of tumor adaptive resistance could facilitate rationale design of adjunctive immunotherapies that can be synergistically combined with immune checkpoint blockers to more effectively treat cancer.

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LIGHT Delivery to Tumors by Mesenchymal Stem Cells Mobilizes an Effective Antitumor Immune Response

Cited by 44 publications

References 53 publications

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

Immune Checkpoint Blockade and Adaptive Immune Resistance in Cancer

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