Engineered PLGA microparticles for long-term, pulsatile release of STING agonist for cancer immunotherapy

2020 ◽  
Vol 12 (556) ◽  
pp. eaaz6606 ◽  
Author(s):  
Xueguang Lu ◽  
Lei Miao ◽  
Wenting Gao ◽  
Ziqi Chen ◽  
Kevin J. McHugh ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Patient Adherence ◽  
Intratumoral Injection ◽  
Immune Checkpoint Blockade ◽  
Mouse Tumor ◽  
Vascular Networks ◽  
Sting Pathway ◽  
Intratumoral Injections

Activation of the stimulator of interferon gene (STING) pathway within the tumor microenvironment has been shown to generate a strong antitumor response. Although local administration of STING agonists has promise for cancer immunotherapy, the dosing regimen needed to achieve efficacy requires frequent intratumoral injections over months. Frequent dosing for cancer treatment is associated with poor patient adherence, with as high as 48% of patients failing to comply. Multiple intratumoral injections also disrupt the tumor microenvironment and vascular networks and therefore increase the risk of metastasis. Here, we developed microfabricated polylactic-co-glycolic acid (PLGA) particles that remain at the site of injection and release encapsulated STING agonist as a programmable sequence of pulses at predetermined time points that mimic multiple injections over days to weeks. A single intratumoral injection of STING agonist–loaded microparticles triggered potent local and systemic antitumor immune responses, inhibited tumor growth, and prolonged survival as effectively as multiple soluble doses, but with reduced metastasis in several mouse tumor models. STING agonist–loaded microparticles improved the response to immune checkpoint blockade therapy and substantially decreased the tumor recurrence rate from 100 to 25% in mouse models of melanoma when administered during surgical resection. In addition, we demonstrated the therapeutic efficacy of STING microparticles on an orthotopic pancreatic cancer model in mice that does not allow multiple intratumoral injections. These findings could directly benefit current STING agonist therapy by decreasing the number of injections, reducing risk of metastasis, and expanding its applicability to hard-to-reach cancers.

scholarly journals In Vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target

2020 ◽  
Author(s):  
Xiaoqing Wang ◽  
Collin Tokheim ◽  
Binbin Wang ◽  
Shengqing Stan Gu ◽  
Qin Tang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Large Scale ◽  
Integrated Approach ◽  
Immune Checkpoint Blockade ◽  
Macrophage Infiltration ◽  
List Type

SUMMARYDespite remarkable clinical efficacies of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits in triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that inhibition of the E3 ubiquitin ligase Cop1 in cancer cells decreases the secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, and shows synergy in anti-tumor immunity with ICB. Transcriptomics, epigenomics, and proteomics analyses revealed Cop1 functions through proteasomal degradation of the C/ebpδ protein. Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. Cop1 inhibition stabilizes C/ebpδ to suppress the expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy by regulating chemokine secretion and macrophage levels in the TNBC tumor microenvironment.HighlightsLarge-scale in vivo CRISPR screens identify new immune targets regulating the tumor microenvironmentCop1 knockout in cancer cells enhances anti-tumor immunityCop1 modulates chemokine secretion and macrophage infiltration into tumorsCop1 targets C/ebpδ degradation via Trib2 and influences ICB response

scholarly journals Searching for Promoters to Drive Stable and Long-Term Transgene Expression in Fibroblasts for Syngeneic Mouse Tumor Models

2020 ◽  
Vol 21 (17) ◽  
pp. 6098
Author(s):  
Dina V. Antonova ◽  
Irina V. Alekseenko ◽  
Anastasiia K. Siniushina ◽  
Alexey I. Kuzmich ◽  
Victor V. Pleshkan
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transgene Expression ◽  
Close Contact ◽  
Mouse Tumor ◽  
Cancer Associated Fibroblasts

Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs are more stable than cancer cells, making them an attractive target for genetic modification in gene therapy. However, the efficiency of various promoters for transgene expression in fibroblasts is scarcely studied. We performed a comparative analysis of transgene long-term expression under the control of strong cytomegalovirus promoter (pCMV), constitutive cell promoter of the PCNA gene (pPCNA), and the potentially fibroblast-specific promoter of the IGFBP2 gene (pIGFBP2). In vitro expression of the transgene under the control of pCMV in fibroblasts was decreased soon after transduction, whereas the expression was more stable under the control of pIGFBP2 and pPCNA. The efficiency of transgene expression was higher under pPCNA than that under pIGFBP2. Additionally, in a mouse model, pPCNA provided more stable and increased transgene expression in fibroblasts as compared to that under pCMV. We conclude that PCNA promoter is the most efficient for long-term expression of transgenes in fibroblasts both in vitro and in vivo.

scholarly journals Targeting the Tumor Microenvironment for Improving Therapeutic Effectiveness in Cancer Immunotherapy: Focusing on Immune Checkpoint Inhibitors and Combination Therapies

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1188
Author(s):  
I-Tsu Chyuan ◽  
Ching-Liang Chu ◽  
Ping-Ning Hsu
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints

Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy.

scholarly journals Tumour neoantigen mimicry by microbial species in cancer immunotherapy

2021 ◽  
Author(s):  
Maximilian Boesch ◽  
Florent Baty ◽  
Sacha I. Rothschild ◽  
Michael Tamm ◽  
Markus Joerger ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Molecular Mimicry ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Molecular Fingerprint ◽  
Microbial Species ◽  
Anti Cancer

AbstractTumour neoantigens arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer. Although this fingerprint perfectly discriminates cancer from healthy somatic and germline cells, and is therefore therapeutically exploitable using immune checkpoint blockade, gut and extra-gut microbial species can independently produce epitopes that resemble tumour neoantigens as part of their natural gene expression programmes. Such tumour molecular mimicry is likely not only to influence the quality and strength of the body’s anti-cancer immune response, but could also explain why certain patients show favourable long-term responses to immune checkpoint blockade while others do not benefit at all from this treatment. This article outlines the requirement for tumour neoantigens in successful cancer immunotherapy and draws attention to the emerging role of microbiome-mediated tumour neoantigen mimicry in determining checkpoint immunotherapy outcome, with far-reaching implications for the future of cancer immunotherapy.

scholarly journals Chromatin-Bound PARP1 Correlates with Upregulation of Inflammatory Genes in Response to Long-Term Treatment with Veliparib

2020 ◽  
Author(s):  
Isabel Alvarado-Cruz ◽  
Mariam Mahmoud ◽  
Mohammed Khan ◽  
Shilin Zhao ◽  
Sebastian Oeck ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Term Treatment ◽  
Inflammatory Genes ◽  
Homology Directed Repair ◽  
Long Term Treatment ◽  
Sting Pathway

AbstractPoly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat human HCC1937 BRCA1 mutant and isogenic BRCA1-complemented cells for three weeks with veliparib, a PARP inhibitor. We show that long-term treatment with veliparib results in chromatin-bound PARP1 in the BRCA1 mutant cells, and that this correlates with significant upregulation of inflammatory genes and activation of the cyclic GMP–AMP synthase (cGAS)/ signalling effector stimulator of interferon genes (STING) pathway. In contrast, long-term treatment of isogenic BRCA1-complemented cells with veliparib does not result in chromatin-associated PARP or significant upregulation of the inflammatory response. Our results suggest that long-term veliparib treatment may prime BRCA1 mutant tumors for positive responses to immune checkpoint blockade.

scholarly journals ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

2020 ◽  
Vol 117 (33) ◽  
pp. 20159-20170 ◽  
Author(s):  
Na Li ◽  
Yuqi Kang ◽  
Lingling Wang ◽  
Sarah Huff ◽  
Rachel Tang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Therapy Response ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Potential Therapeutic Target ◽  
Cell Accumulation ◽  
Melanoma Patients ◽  
Expression Status

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB.N6-methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.

scholarly journals The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment

2021 ◽  
Vol 6 (7) ◽  
pp. 1973-1987
Author(s):  
Muyue Yang ◽  
Jipeng Li ◽  
Ping Gu ◽  
Xianqun Fan
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy

scholarly journals Magnetic Nanostructures as Emerging Therapeutic Tools to Boost Anti-Tumour Immunity

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2735
Author(s):  
Stefano Persano ◽  
Pradip Das ◽  
Teresa Pellegrino
Keyword(s):  
Cancer Immunotherapy ◽  
Low Cost ◽  
Drug Stability ◽  
Adoptive Cell Therapy ◽  
Magnetic Nanostructures ◽  
Immune Checkpoint Blockade ◽  
Therapeutic Vaccines ◽  
Durable Response ◽  
Tumour Immunity ◽  
Therapeutic Modalities

Cancer immunotherapy has shown remarkable results in various cancer types through a range of immunotherapeutic approaches, including chimeric antigen receptor-T cell (CAR-T) therapy, immune checkpoint blockade (ICB), and therapeutic vaccines. Despite the enormous potential of cancer immunotherapy, its application in various clinical settings has been limited by immune evasion and immune suppressive mechanisms occurring locally or systemically, low durable response rates, and severe side effects. In the last decades, the rapid advancement of nanotechnology has been aiming at the development of novel synthetic nanocarriers enabling precise and enhanced delivery of immunotherapeutics, while improving drug stability and effectiveness. Magnetic nanostructured formulations are particularly intriguing because of their easy surface functionalization, low cost, and robust manufacturing procedures, together with their suitability for the implementation of magnetically-guided and heat-based therapeutic strategies. Here, we summarize and discuss the unique features of magnetic-based nanostructures, which can be opportunely designed to potentiate classic immunotherapies, such as therapeutic vaccines, ICB, adoptive cell therapy (ACT), and in situ vaccination. Finally, we focus on how multifunctional magnetic delivery systems can facilitate the anti-tumour therapies relying on multiple immunotherapies and/or other therapeutic modalities. Combinatorial magnetic-based therapies are indeed offering the possibility to overcome current challenges in cancer immunotherapy.

scholarly journals Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tiecheng Wang ◽  
Jiakang Jin ◽  
Chao Qian ◽  
Jianan Lou ◽  
Jinti Lin ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Immune Cells ◽  
Target Genes ◽  
Target Therapy ◽  
Treatment Strategies ◽  
Signal Transduction Pathway ◽  
Pathway Activation ◽  
Immune System Regulation

AbstractAs the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies.

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