Intratumoral immunotherapy using a TLR2/3 agonist, L-pampo, induces robust antitumor immune responses and enhances immune checkpoint blockade

Lee, Won Suk; Kim, Dong Sung; Kim, Jeong Hun; Heo, Yoonki; Yang, Hannah; Go, Eun-Jin; Kim, Jin Hyoung; Lee, Seung Joon; Ahn, Byung Cheol; Yum, Jung Sun; Chon, Hong Jae; Kim, Chan

doi:10.1136/jitc-2022-004799

Cited by 16 publications

(10 citation statements)

References 50 publications

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“…As reported previously, 12 genes (HMGB1, ATG5, TLR2, CD4, PRF1, BAX, EGFR, IFNG, ATG7, TLR4, CD8B, and AXL) were demonstrated to be associated with ICD [17][18][19][20][21][22]. Firstly, the expression patterns of the above 12 ICD-associated genes were comparatively assessed in ccRCC and normal tissue samples obtained from the TCGA and GTEx databases.…”

Section: Differentially Expressed Icd-related Genes Between Ccrcc And...mentioning

confidence: 89%

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TLR4 predicts patient prognosis and immunotherapy efficacy in clear cell renal cell carcinoma

Zhang¹,

Lu²,

Xia³

et al. 2023

J. Cancer

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Background: Clear cell renal cell carcinoma (ccRCC) constitutes the commonest kidney malignancy. Immunogenic cell death (ICD) is a type of regulated cell death (RCD), which sufficiently activates adaptive immunity. However, ICD's involvement in cancer development is unclear, as well as the associations of ICD effectors with ccRCC prognosis. Methods: RNA-sequencing expression profiles of ccRCC in The Cancer Genome Atlas (TCGA) and normal samples in Gene Expression Omnibus (GEO) were comprehensively investigated. Consensus clustering analysis was employed to determine subgroup members linked to ICD-related genes. Functional enrichment analysis was utilized for the examination of TLR4's biological role, and in vitro cellular assays were utilized for further confirmation. We also used Kaplan-Meier (KM) and Cox regression analyses to assess TLR4's prognostic value. Finally, "CIBERSORT" was employed for immune score evaluation. Results: The associations of ICD effectors with ccRCC prognosis were examined based on TCGA, and 12 genes showed upregulation in ccRCC tissue specimens. Meanwhile, ccRCC cases with upregulated ICD-related genes had increased overall survival. Among these ICD-related genes, TLR4 was selected for subsequent analysis. TLR4 was upregulated in ccRCC samples and independently predicted ccRCC. TLR4 also enhanced the proliferative, migratory and invasive abilities in cultured ccRCC cells. Moreover, TLR4 had close relationships with immune checkpoints and infiltrated immune cells. ccRCC cases with elevated TLR4 expression had prolonged overall survival, suggesting a prognostic value for TLR4. Finally, a pan-cancer analysis demonstrated TLR4 had differential expression in various malignancies in comparison with normal tissue samples. Conclusions: This study revealed prognostic values for ICD-associated genes, particularly TLR4, and experimentally validated the inducing effects of TLR4 on ccRCC progression in vitro. We also demonstrated the associations of TLR4 with immune cell infiltration, providing a novel strategy for prognostic evaluation and a novel therapeutic target in ccRCC.

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Section: Differentially Expressed Icd-related Genes Between Ccrcc And...mentioning

confidence: 89%

“…ICD-associated genes were retrieved from previously published reports [17][18][19][20][21][22]. TLR4 protein levels measured by immunohistochemistry in tumor and paired normal tissues were retrieved from Human Protein Atlas (https://www.proteinatlas .org/).…”

Section: Data Collection and Processingmentioning

confidence: 99%

TLR4 predicts patient prognosis and immunotherapy efficacy in clear cell renal cell carcinoma

Zhang¹,

Lu²,

Xia³

et al. 2023

J. Cancer

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“…64 Importantly, multiple TLR agonists have been investigated in combination with CPI to enhance efficacy across various cancer types. [65][66][67][68] Furthermore, of the genes identified to decrease in expression on-CPI in breast cancer, PIK3R2 was already lowly expressed in melanoma tumors pre-therapy and has been associated with repressed cell proliferation, invasion, epithelial-mesenchymal transition, and cell apoptosis in melanoma cells, 69 which could hold potential applicability in breast cancer. These genes warrant further investigation and may be potential targets for combination therapy in IO refectory cancers like TNBC, particularly genes such as TLR8, TLR4, and TLR1, which are known IO targets.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the impact of immunotherapy on RNA dynamics in cancer

Usaite,

Biswas,

Dijkstra

et al. 2023

J Immunother Cancer

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BackgroundCheckpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance.MethodsWe assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies.ResultsMeta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptorsTLR1,TLR4, andTLR8, that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types.ConclusionsOverall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy.

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“…In addition, intratumoral injection of immunostimulatory agents has shown synergistic effects with other immunotherapies, including ICIs [188]. For example, intratumoral injection of L-pampo, a TLR2/3 agonist, induced a potent T helper cell-mediated immune response and immunogenic tumor cell death, which increased the efficacy of αPD-1 and αCTLA-4 therapies [189]. Currently, many clinical trials are ongoing to evaluate the therapeutic effect of this treatment option and its synergistic effects.…”

Section: Frontiers and Prospectsmentioning

confidence: 99%

Cancer Immunotherapy and Delivery System: An Update

et al. 2022

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With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a powerful tool in the clinic to treat many cancers. The strategies applied in cancer immunotherapy mainly include blockade of immune checkpoints, adoptive transfer of engineered cells, such as T cells, natural killer cells, and macrophages, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors, such as product price, off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity, affect the treatment efficacy of immunotherapies against cancers. In addition, some treatments, such as chimeric antigen receptor (CAR) T cell therapy, are more effective in treating patients with lymphoma, leukemia, and multiple myeloma rather than solid tumors. To improve the efficacy of targeted immunotherapy and reduce off-target effects, delivery systems for immunotherapies have been developed in past decades using tools such as nanoparticles, hydrogel matrix, and implantable scaffolds. This review first summarizes the currently common immunotherapies and their limitations. It then synopsizes the relative delivery systems that can be applied to improve treatment efficacy and minimize side effects. The challenges, frontiers, and prospects for applying these delivery systems in cancer immunotherapy are also discussed. Finally, the application of these approaches in clinical trials is reviewed.

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Intratumoral immunotherapy using a TLR2/3 agonist, L-pampo, induces robust antitumor immune responses and enhances immune checkpoint blockade

Cited by 16 publications

References 50 publications

TLR4 predicts patient prognosis and immunotherapy efficacy in clear cell renal cell carcinoma

TLR4 predicts patient prognosis and immunotherapy efficacy in clear cell renal cell carcinoma

Quantifying the impact of immunotherapy on RNA dynamics in cancer

Cancer Immunotherapy and Delivery System: An Update

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