Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis

Ding, Chuan‐Fan; Shrestha, Rejeena; Zhu, Xiaojuan; Geller, Anne E; Wu, Shouzhen; Woeste, Matthew R; Li, Wenqian; Wang, Haomin; Yuan, Fang; Xu, Raobo; Chariker, Julia H.; Hu, Xiaoling; Li, Hong; Tieri, David; Zhang, Huang‐Ge; Rouchka, Eric C.; Mitchell, Robert A.; Siskind, Leah J.; Zhang, Xiang; Xu, Xiaoji G.; McMasters, Kelly M.; Yu, Yan; Yan, Jun

doi:10.1038/s41590-022-01388-8

Cited by 63 publications

(44 citation statements)

References 53 publications

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“…β-Glucan trained mice induced lung interstitial macrophage training and reduced lung metastasis in NSG mice. 49 Moreover, we have also previously observed myeloid cell training in the murine pancreas after monoclonal antibody depletion of NK cells as well as in NSG mice. 26 Collectively, these data suggest that NK cells may not play an essential role in this combination therapy.…”

Section: Discussionmentioning

confidence: 81%

“…23 Antitumor immune effects of trained immunity agonists have only recently been described in both prevention and treatment. [47][48][49] However, no studies have discussed or demonstrated methods to provoke or augment the level of trained response. A unique finding from our study is that supernatant derived from IRE ablated cancer cells incited a more potent trained response from β-glucan trained myeloid cells compared with tumor-conditioned media alone.…”

Section: Discussionmentioning

confidence: 99%

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Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma

Woeste

Shrestha

Geller

et al. 2023

J Immunother Cancer

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BackgroundPancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC.Methodsβ-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag−/−mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry.ResultsIRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE.ConclusionsThese data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma

Woeste

Shrestha

Geller

et al. 2023

J Immunother Cancer

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“…In particular, intraperitoneal administration of whole b-glucan particles to mice, followed by intravenous injection 7 days later of lung Lewis carcinoma cells, induces BM myelopoiesis and MO activation, leading to the control of metastasis. In this case, the alveolar niche is not depleted, but the trained-MOs differentiate into MO-IMs without contributing to the AM pool, potentially explaining why only IM-MO are associated with reduced tumour development (176). The specific contribution of virus-trained AMs in anti-tumor immunity has been recently investigated in an elegant study published by Wang et al (177).…”

Section: Peripheral or Central Imprinting: How Does Immune Reprogramm...mentioning

confidence: 99%

“…In contrast, epigenetic rewiring of HSCs following microbial or nanobiologics exposure enhances myelopoiesis and macrophage activation, which improves therapeutic outcomes in a mouse melanoma model ( 175 ). In addition, a recent study has shown the positive effects of experimental trained immunity in lung macrophages to control metastasis establishment ( 176 ). In particular, intraperitoneal administration of whole β-glucan particles to mice, followed by intravenous injection 7 days later of lung Lewis carcinoma cells, induces BM myelopoiesis and MO activation, leading to the control of metastasis.…”

Section: Peripheral or Central Imprinting: How Does Immune Reprogramm...mentioning

confidence: 99%

Shaping of the alveolar landscape by respiratory infections and long-term consequences for lung immunity

2023

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Respiratory infections and especially viral infections, along with other extrinsic environmental factors, have been shown to profoundly affect macrophage populations in the lung. In particular, alveolar macrophages (AMs) are important sentinels during respiratory infections and their disappearance opens a niche for recruited monocytes (MOs) to differentiate into resident macrophages. Although this topic is still the focus of intense debate, the phenotype and function of AMs that recolonize the niche after an inflammatory insult, such as an infection, appear to be dictated in part by their origin, but also by local and/or systemic changes that may be imprinted at the epigenetic level. Phenotypic alterations following respiratory infections have the potential to shape lung immunity for the long-term, leading to beneficial responses such as protection against allergic airway inflammation or against other infections, but also to detrimental responses when associated with the development of immunopathologies. This review reports the persistence of virus-induced functional alterations in lung macrophages, and discusses the importance of this imprinting in explaining inter-individual and lifetime immune variation.

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“…The formation of immunological memory and the recall response are classic features of the adaptive immune system. Interestingly, there is some evidence of “trained immunity” in macrophages wherein prior exposure to pathogens increases their subsequent ability to control tumor growth 77,78 . These emerging characteristics could also potentially be utilized to enhance macrophage‐based therapy for cancer.…”

Section: Tumor‐infiltrating Myeloid Cellsmentioning

confidence: 99%

Good CARMA: Turning bad tumor‐resident myeloid cells good with chimeric antigen receptor macrophages

Snyder

Gill

2023

Immunological Reviews

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SummaryIn religious philosophy, the concept of karma represents the effect of one's past and present actions on one's future. Macrophages are highly plastic cells with myriad roles in health and disease. In the setting of cancer, macrophages are among the most plentiful members of the immune microenvironment where they generally support tumor growth and restrain antitumor immunity. However, macrophages are not necessarily born bad. Macrophages or their immediate progenitors, monocytes, are induced to traffic to the tumor microenvironment (TME) and during this process they are polarized toward a tumor‐promoting phenotype. Efforts to deplete or repolarize tumor‐associated macrophages (TAM) for therapeutic benefit in cancer have to date disappointed. By contrast, genetic engineering of macrophages followed by their transit into the TME may allow these impressionable cells to mend their ways. In this review, we summarize and discuss recent advances in the genetic engineering of macrophages for the treatment of cancer.

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Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis

Cited by 63 publications

References 53 publications

Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma

Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma

Shaping of the alveolar landscape by respiratory infections and long-term consequences for lung immunity

Good CARMA: Turning bad tumor‐resident myeloid cells good with chimeric antigen receptor macrophages

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