Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery

Chen, Binfan; Gao, Ang; Tu, Bin; Wang, Yonghui; Yu, Xiaolu; Wang, Yingshu; Xiu, Yan-Feng; Wang, Bing; Wan, Yakun; Huang, Yongzhuo

doi:10.1016/j.biomaterials.2020.120187

Cited by 91 publications

(70 citation statements)

References 39 publications

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“…The TAT-BLZmlips were characterized by three advantages: 1) magnetic navigation for targeting delivery; 2) MHT effect; and 3) codelivery of a CSF-1R inhibitor for immunotherapy. CT26 colon cancer is characterized by microsatellite stability and the consequent less-immunogenic nature 28 , 29 , which is often used as a “cold” tumor model 30 . The treatment regimen in the mice bearing CT26 tumor is shown in Figure 4 A.…”

Section: Resultsmentioning

confidence: 99%

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

Fang

et al. 2021

Theranostics

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Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called “cold” tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in “cold” colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an “eat-me” signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8 + T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.

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Section: Resultsmentioning

confidence: 99%

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

Fang

et al. 2021

Theranostics

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“…Indeed, immune cells are capable of sensing various signals in the microenvironment and turning on specific immune functions in response. More and more evidences have pointed out that the immune response is associated with dramatic modifications in tissue metabolism, including the depletion of nutrients, increased oxygen consumption, and the generation of reactive nitrogen and oxygen intermediates [10][11][12]. Similarly, many metabolites in the tumor microenvironment, in turn, also influence immune cell differentiation and effector function [13,14].…”

Section: Introductionmentioning

confidence: 99%

The cancer metabolic reprogramming and immune response

et al. 2021

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The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.

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“…A nanoplatform was developed by integrating modified graphene oxide, nitrogen-doped carbon dots, and hydroxyapatite to normalize the blood vessels while relieving immune-related adverse events. [79] Moreover, siRNA-conjugated polymeric NPs, [80] the anti-angiogenic drug (i.e., regorafenib)encapsulated liposomal platform, [81] and angiogenin-binding nanofiber, have been demonstrated to normalize TIME. [82] Taken together, the blood flow and perfusion are disturbed because of abnormalities in tumor blood vessels, which negatively affects drug delivery and hence reduces the therapeutic efficacy.…”

Section: Normalization Of Tumor Vasculaturesmentioning

confidence: 99%

From Design to Clinic: Engineered Nanobiomaterials for Immune Normalization Therapy of Cancer

Saeed

Chen

et al. 2021

Advanced Materials

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is actively involved in T cell exhaustion. TIME is comprised of various stromal cells, extracellular matrix (ECM), innate and adaptive immune cells, (such as, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and dendritic cells (DCs)), abnormal blood and lymphatic vessels, acidic pH, hypoxia, and high interstitial fluid pressure, that contribute to stunting antitumor immune response. [2] Moreover, immune checkpoints and negative regulatory pathways, for example, programmed cell death receptor 1 (PD1) and its ligand (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and transforming growth factor β (TGF-β) are the main culprits in TIME that promote T cell exhaustion and adaptive resistance. [3] The considerable level of interplay, complicity, and crosstalk between tumor and immune cells further adds complexity to TIME. A deeper understanding of TIME, however, is urgently needed to deal with the key mechanisms underlying the ability of TIME to evade antitumor immunity.The failure of current immunotherapeutics, such as, antibodies, immune checkpoint inhibitors, cytokines, and agonists, to target the TIME because of its complex milieu leads to tumor progression and metastasis. Preclinical and clinical studies suggest that therapeutic drugs drive cascades of systemic toxicityThe tumor immune microenvironment (TIME) is comprised of a complex milieu that contributes to stunting antitumor immune responses by restricting T cells to accumulate in the vicinity of the tumor. Nanomedicinebased strategies are being proposed as a salvage effort to reinvigorate antitumor immunity. Various strategies, however, often fail to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex TIME, invigorating a fervor of investigation into mechanisms underlying the TIME to resist nanomedicines. In this review article, effective nano/biomaterial-based delivery and TIME normalization approaches that promote T cell-mediated antitumor immune response will be discussed, with a focus on emerging preclinical and clinical strategies for immune normalization. Based on currently available evidence, it seems as if the ultimate success of cancer immunotherapy and nanomedicine hinges on the capacity to normalize the TIME. Here, how nanomedicines target immunosuppressive cells and signaling pathways to broaden the impact of cancer immunotherapy are explored. Acquisition of the urgently needed knowledge of nanomedicine-mediated immune normalization will guide researchers and scientists towards clinical applications of cancer immunotherapy.

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Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery

Cited by 91 publications

References 39 publications

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

The cancer metabolic reprogramming and immune response

From Design to Clinic: Engineered Nanobiomaterials for Immune Normalization Therapy of Cancer

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