In situ antitumor vaccination: Targeting the tumor microenvironment

Li, Hanwen; Yu, Jiayun; Wu, Yongyao; Shao, Bin; Wei, Xiawei

doi:10.1002/jcp.29551

Cited by 23 publications

(16 citation statements)

References 115 publications

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“…However systemically administration was limited by systemic toxicity and other side effects. On the contrary, intratumor injection might minimize drug dose, reduce systemic side effects and optimize distribution of drug to the target site ( 42 ). Importantly, intratumoral therapy could alter the tumor microenvironment from immunosuppressive to immunostimulatory and generate systemic T cell responses.…”

Section: Discussionmentioning

confidence: 99%

Targeting the MDSCs of Tumors In Situ With Inhibitors of the MAPK Signaling Pathway to Promote Tumor Regression

Zhang

et al. 2021

Front. Oncol.

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Myeloid-derived suppressor cells (MDSCs) are one of the major components of the tumor microenvironment. Evidence has shown differences in the functions and fates of MDSCs in the tumor tissue and the periphery. However, the exact mechanism that regulates MDSC function has not been completely clarified. In this study, we performed RNA sequencing of MDSCs derived from the spleen and tumor. Based on the results of our RNA-seq analysis, mitogen-activated protein kinases (MAPK) were significantly increased in tumor polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). Subsequently, 3 major MAPK pathways, including extracellular signal-regulated protein kinases (ERK), p38 and c-Jun NH2-terminal kinases (JNK), were studied to analyze the role of MAPKs in MDSCs. The ERK 1/2 inhibitor SCH772984 and the JNK inhibitor SP600125 significantly increased the apoptosis of both PMN-MDSCs and M-MDSCs in vitro. In addition, SCH772984 exerted a strong effect on inhibiting tumor growth. The flow cytometry analysis showed significant increases in the ratio of M1:M2 tumor-associated macrophages, meanwhile the number of CD4+, CD8+, CD4+CD69+ and CD8+CD69+ lymphocytes were increased after SCH772984 treatment. Our findings established the effect of MAPKs on the tumor microenvironment via MDSCs and may facilitate the development of new antitumor strategies.

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Section: Discussionmentioning

confidence: 99%

Targeting the MDSCs of Tumors In Situ With Inhibitors of the MAPK Signaling Pathway to Promote Tumor Regression

Zhang

et al. 2021

Front. Oncol.

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“…The development of combinatorial therapies for mCRC is being actively sought since monotherapies have not demonstrated effectiveness in improving patient's outcome (10). Since tumors evolved multiple mechanisms to avoid immune evasion, a multi-faceted approach focusing on different mechanisms will most likely be needed to address current issues in CRC treatment (10,199,(221)(222)(223).…”

Section: Reverting DC Dysfunction To Unleash Anti-tumor Immunity and Response To Immunotherapymentioning

confidence: 99%

The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer

Subtil¹,

Cambi²,

Tauriello³

et al. 2021

Front. Immunol.

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Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.

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“…[ 1 ] In situ tumor vaccination seeks to enhance the immunogenicity of tumor cells and prime systemic antitumor immune response against primary and metastatic tumors. [ 2 ] Different from conventional vaccines, in situ vaccination could conveniently convert established tumors into a “vaccine factory” to release various tumor antigens for stimulating and diversifying antitumor T‐cell response. [ 3 ] Radiation therapy (RT) is a widely used local therapy of malignancies and exhibits great potential in inducing in situ tumor vaccine effect.…”

Section: Introductionmentioning

confidence: 99%

High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

et al. 2022

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Different from conventional vaccines, in situ vaccination could conveniently convert established tumors into a "vaccine factory" to release various tumor antigens for stimulating and diversifying antitumor T-cell response. [3] Radiation therapy (RT) is a widely used local therapy of malignancies and exhibits great potential in inducing in situ tumor vaccine effect. [4] However, even potentiated by CBI, RT could only lead to mild to moderate immune response within nonirradiated tumors, which is far less than medical needs. [5] Therefore, it is quite meaningful to boost RT-mediated in situ vaccination to extend its therapeutic effect to the whole body.To achieve this goal, a possible way could be potentiating RT-induced immunogenic cell death (ICD). ICD is a death modality accompanied by releasing tumor antigens and damage-associated molecular patterns, including calreticulin (CRT), high mobility group protein B1 (HMGB1), etc., which could provide antigens and adjuvants for tumor vaccination. [6] Currently, some studies have indicated that oxidative stress and DNA damage within tumor cells could potentially result in ICD. [7] However, due to the insufficient deposition of X-ray within tumor tissues, only low level of reactive oxygen species (ROS) could be produced to induce oxidative stress upon the recommended radiation doses. To address this problem, radiosensitizers based on high-Z elements are being developed widely to deposit X-ray for amplifying RT-induced oxidative stress. Of note, HfO 2 nanoparticles (Hensify) have been approved in Europe for locally advanced soft tissue sarcoma treatment [8] and are confirmed to augment RT-mediated antitumor immunity effect in many clinical trials. However, their slight improvements suggest the room for optimization. [9] The pentose phosphate pathway (PPP) is a branch of glycolysis and hyperactive in most tumors, [10] which could provide abundant NADPH and ribose 5-phosphate to maintain redox and nucleotides homeostasis, respectively. [11] NADPH is a central player in cellular antioxidant system, which not only mediates GSH synthesis, [12] but also acts as an electron donor to reduce oxidized GSH and thioredoxin (Trx, an important In situ tumor vaccination is preliminarily pursued to strengthen antitumor immune response. Immunogenic tumor cell death spontaneously releases abundant antigens and adjuvants for activation of dendritic cells, providing a paragon opportunity for establishing efficient in situ vaccination. Herein, Phy@PLGdH nanosheets are constructed by integrating physcion (Phy, an inhibitor of the pentose phosphate pathway (PPP)) with layered gadolinium hydroxide (PLGdH) nanosheets to boost radiation-therapy (RT)-induced immunogenic cell death (ICD) for potent in situ tumor vaccination. It is first observed that sheet-like PLGdH can present superior X-ray deposition and tumor penetrability, exhibiting improved radiosensitization in vitro and in vivo. Moreover, the destruction of cellular nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotide...

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In situ antitumor vaccination: Targeting the tumor microenvironment

Cited by 23 publications

References 115 publications

Targeting the MDSCs of Tumors In Situ With Inhibitors of the MAPK Signaling Pathway to Promote Tumor Regression

Targeting the MDSCs of Tumors In Situ With Inhibitors of the MAPK Signaling Pathway to Promote Tumor Regression

The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer

High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

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