Immunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors

Duan, Xiaopin; Chan, Cheeling; Han, Wenbo; Guo, Nining; Weichselbaum, Ralph R.; Lin, Wenbin

doi:10.1038/s41467-019-09221-x

Cited by 215 publications

(162 citation statements)

References 62 publications

(51 reference statements)

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“…Recent studies have shown that the immune status of the tumor microenvironment is an essential factor affecting tumor progression. 4,[6][7][8] Both innate and adaptive immunity in the tumor microenvironment have been intensively investigated. In recent years, T-cell-based immunotherapy has shown benefits and provided hope for countless patients.…”

Section: Introductionmentioning

confidence: 99%

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

Wang

Luo

Chen

et al. 2020

Sig Transduct Target Ther

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The inhibitory receptor signal regulatory protein-α (Sirpα) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47, which is expressed on tumor and normal tissue cells. However, the profile and regulatory mechanism of Sirpα expression in tumor-associated macrophages (TAMs) are still not clear. Here, we found that the expression of Sirpα in TAMs increased dynamically with colorectal cancer (CRC) progression. Mechanistically, CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2α from the cytoplasm in TAMs. Ap-2α functioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at −1396/−1391 in the mouse Elk-1 promoter. Subsequently, the Elk-1 protein bound to two conserved sites, CTTCCTACA (located at −229/−221) and CTTCCTCTC (located at −190/−182), in the mouse Sirpα promoter and promoted Sirpα expression in TAMs. Functionally, the macrophage-specific knockout of Ap-2α notably promoted the phagocytic activity of TAMs and suppressed CRC progression, whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1, which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner. Furthermore, we showed that Elk-1 expression was positively correlated with Sirpα expression in TAMs and was associated with poor survival in CRC patients. Taken together, our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.Signal Transduction and Targeted Therapy (2020) 5:35; https://doi.

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Section: Introductionmentioning

confidence: 99%

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

Wang

Luo

Chen

et al. 2020

Sig Transduct Target Ther

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“…Just to mention one example, dihydroartemisinin (DHA), a widely employed drug to treat malaria, contains a peroxide bridge that produces ROS in the presence of Fe 2+ as a catalyst. This drug has been co-delivered in combination with oxalilplatin in a controlled manner in solid tumors employing coordination polymer-based nanoparticles [81]. DHA release induced ROS formation within the tumoral cells, which altered their cell surface composition, causing CRT exposition and DAMP secretion, which enhanced APC recruitment.…”

Section: Nanoparticles To Enhance the Antitumoral Action Of Adaptive mentioning

confidence: 99%

“…The most representative nanocarriers described in this section are represented in Table 2. [74] Enhanced survival of T cells Self-assembled amphiphilic peptide IDO inhibitors and PD-L1 antagonist Melanoma [75] Higher expression of CRT, TNF-α, INF-γ and IL-6 -higher APC maturation and higher T cell activation and infiltration Core-shell coordination polymers Photosensitizer/oxalilplatin and anti-PD-L1 Colorectal cancer [78] ROS generation which enhances expression CRT -T cell activation, memory effect coordination polymer Dihydroartemisinin and anti-PD-L1 Colorectal cancer [81] ICD tumoral cells, higher T cell activation and infiltration PLGA-PEI-PEG Dox and microRNA that silence PD-L1 Colon adenocarcinoma [82] Improve CD8+ T cell infiltration Lipid-dendrimer-calcium-phosphate siRNA that silence PD-L1 and plasmid encoding IL-2…”

Section: Nanoparticles To Enhance the Antitumoral Action Of Adaptive mentioning

confidence: 99%

Tumor Targeted Nanocarriers for Immunotherapy

Baeza

2020

Molecules

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The paramount discovery of passive accumulation of nanoparticles in tumoral tissues triggered the development of a wide number of different nanoparticles capable of transporting therapeutic agents to tumoral tissues in a controlled and selective way. These nanocarriers have been endowed with important capacities such as stimuli-responsive properties, targeting abilities, or the capacity to be monitored by imaging techniques. However, after decades of intense research efforts, only a few nanomedicines have reached the market. The reasons for this disappointing outcome are varied, from the high tumor-type dependence of enhanced permeation and retention (EPR) effect to the poor penetration capacity of nanocarriers within the cancerous tissue, among others. The rapid nanoparticle clearance by immune cells, considered another important barrier, which compromises the efficacy of nanomedicines, would become an important ally in the fight against cancer. In the last years, the fine-tuned ability of immune cells to recognize and engulf nanoparticles have been exploited to deliver immunoregulating agents to specific immune cell populations selectively. In this work, the recent advances carried out in the development of nanocarriers capable of operating with immune and tumoral cells in order to orchestrate an efficient antitumoral response will be presented. The combination of nanoparticles and immunotherapy would deliver powerful weapons to the clinicians that offer safer and more efficient antitumoral treatments for the patients.

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“…In recent years, immunotherapy has been explored as a therapeutic treatment for CRC. Studies have shown that several immune cells modulate CRC response by infiltrating the CRC microenvironment [3,4]. Among these immune cells, type 2 innate lymphoid cells (ILC2s) are abundant in the gut to regulate the gut homeostasis [5,6].…”

Section: Introductionmentioning

confidence: 99%

ILC2-derived IL-9 inhibit s colorectal cancer progression by activating CD8+ T cells

Wan

Huang

et al. 2020

Preprint

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Background Type 2 innate lymphoid cells (ILC2s), characterized by secreting type 2 cytokines, regulate multiple immune responses. ILC2s are found in different tumor tissues and ILC2-derived interleukin (IL)-4, IL-5, and IL-13 act on the cells in tumor microenvironment to participate in tumor progression. ILC2s are abundant in colorectal cancer (CRC) tissue, but the role of ILC2s in CRC remains unclear. Methods ILC2s were sorted from the spleen using microbeads combined with flow cytometry and tumor infiltrating CD8+ T cells were isolated from tumor tissue by microbeads. Flow cytometry and immunofluorescence were used to detect the percentage of ILC2s and CD8+ T cells in the spleen and CRC tissue. Effects of IL-9 and IL-9-stimulated CD8+ T cells on CT26 cells were measured by proliferation, apoptosis, and migration assays in vitro. GEPIA was used to detect the ILC2s chemokines in CRC tissue and adjacent normal tissue. Results We found that ILC2s were increased in CRC tissue compared with the adjacent normal tissue. In vitro experiments showed that IL-9 could activate CD8+ T cells to promote the death of CT26 cells. ILC2s were the main IL-9-secreting cells in CRC tissue as shown by flow cytometry analysis. In vivo experiments showed that neutralizing ILC2s promoted the tumor growth, while tumor inhibition occurred by intravenous injection of IL-9. Conclusions Our results demonstrated that ILC2-derived IL-9 activated CD8+ T cells to promote anti-tumor effects in CRC.

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Immunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors

Cited by 215 publications

References 62 publications

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

Tumor Targeted Nanocarriers for Immunotherapy

ILC2-derived IL-9 inhibit s colorectal cancer progression by activating CD8+ T cells

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