Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma

Shoushtari, Alexander N.; Olszanski, Anthony J.; Nyakas, Marta; Hornyak, Thomas J.; Wolchok, Jedd D.; Levitsky, Victor; Kuryk, Łukasz; Jäderberg, Magnus

doi:10.1158/1078-0432.ccr-22-2046

Cited by 29 publications

(29 citation statements)

References 39 publications

(45 reference statements)

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“…It has been reported that cancer-associated Macrophage play a key role in tumor progression, angiogenesis, invasion and recruitment of immunosuppressive cells ( Samain and Sanz-Moreno, 2020 ). Persistent immune-related gene expression and T-cell penetration were associated with clinical benefit in SKCM patients ( Shoushtari et al, 2022 ). The infiltrating levels of various effector T cells, such as CD4 + and CD8 + T, were significantly higher in the immune-high group than in the control group.…”

Section: Discussionmentioning

confidence: 99%

Data-driven analysis to identify prognostic immune-related biomarkers in BRAF mutated cutaneous melanoma microenvironment

Huang

2022

Front. Genet.

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Skin cutaneous melanoma is one of the deadly diseases, and more than 50% of the patients have BRAF gene mutations. Evidence suggests that oncogenic BRAF modulates the immune system’s ability to recognize SKCM cells. Due to the complexity of the tumor microenvironment (TME) and a lack of a rational mechanistic basis, it is urgent to investigate the immune infiltration and identify prognostic biomarkers in BRAF mutated SKCM patients. Multiple methods including ESTIMATE algorithm, differential gene analysis, prognostic analysis and immune infiltration analysis were performed to investigate the tumor microenvironment. Based on the patient’s immune score and stromal score, immune-related genes DEGs were identified. Functional analysis revealed that these genes were mainly enriched in biological processes such as immune response, defense response and positive regulation of immune system. Furthermore, we analyzed the immune infiltrating cell components of BRAF mutated patients and revealed 4 hub genes associated with overall survival time. Several cells (Monocyte, Macrophage and Gamma delta cells) have been found to be significantly decreased in immune-high BRAF mutated SKCM group. While CD4+T, CD8+T, CD4 naïve, Tr1, Th2 and many T cell subsets were significantly increased in immune-high group. These immune cells and genes were closely related to each other. This study revealed that the dysregulation of immune function and immune cells may contribute to the poor outcomes of BRAF mutated patients. It is of great significance to our further understanding of the TME and immune dysfunction in BRAF mutated SKCM.

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Section: Discussionmentioning

confidence: 99%

Data-driven analysis to identify prognostic immune-related biomarkers in BRAF mutated cutaneous melanoma microenvironment

Huang

2022

Front. Genet.

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“…However, these regimens are only effective for a subset of patients, with others showing only a limited response or response failure, especially in the advanced stages ( 23 , 24 ). Furthermore, most patients with advanced melanoma do not respond to ICI therapy due to primary or acquired drug tolerance ( 22 , 25 ). Combining anti- CTLA4 and anti- PD - 1 checkpoint inhibitors to enhance antitumor immune reactions, or ICIs combined with intratumoral oncolytic virotherapy, may trigger pro-inflammatory rebuilding of the TME to overcome anti- PD - L1 resistance.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis identifies PSMB8 as a key gene in the cutaneous malignant melanoma tumor microenvironment

Lin¹,

Yu²,

Wang³

et al. 2022

Ann Transl Med

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Background: Cutaneous tumors are commonly seen in clinical practice, and malignant melanoma (MM) is the leading cause of cutaneous tumor-induced death. The tumor microenvironment (TME), a critical part of tumorigenesis, has been a research hotspot in recent years. However, the effects of the MM microenvironment components remain elusive. This study aimed to analyze the various components in the TME of MM to identify factors affecting the tumorigenesis, progression, and metastasis of MM and the survival of MM patients. We also aimed to identify biomarkers related to TME rehabilitation to provide a new direction for MM treatment.Methods: We used bioinformatics to analyze the RNA-seq and somatic mutation data of 473 MM patients from The Cancer Genome Atlas database. Firstly, the patients' immunity and stroma were separately scored by the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) method. According to the median score, the participants were split into high-and low-score groups. Then, Gene Set Enrichment Analysis (GSEA) was performed, showing that high-expression genes were highly abundant in biological and metabolic activities associated with the immune system.Results: Differentially expressed genes (DEGs) and differentially mutated genes (DMGs) were identified and intersected to obtain the key immune-related genes PSMB8, FAM216B, DYSF, and FAM131C. PSMB8 was finally selected as the preferred immune-related prognostic marker; it was positively associated with overall survival and therefore considered a protective gene for MM patients. The GSEA analysis showed that PSMB8 with high expression had greater gene abundance in biological and metabolic processes related to immune system. In addition, CIBERSORT analysis showed an association between the proportion of tumorinfiltrating immune cells and PSMB8 expression.Conclusions: Our results suggest that PSMB8 might be associated with tumorigenesis and MM progression and could serve as a biomarker for the TME rehabilitation of MM. Our findings provide a new perspective and direction for the treatment of MM.

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“…Melanoma oncolysis caused by oncolytic adenovirus can remodel the tumor microenvironment to enhance the efficacy of PD-1 blockade therapy; for example, by leading to the polarization of pro-inflammatory M1-type macrophages, in turn stimulating the proliferation and cytokine production of CD4 + and CD8 + T cells 93 ;…”

Section: Oncolytic and Non-oncolytic Adenovirusmentioning

confidence: 99%

“…Melanoma oncolysis caused by oncolytic adenovirus can remodel the tumor microenvironment to enhance the efficacy of PD‐1 blockade therapy; for example, by leading to the polarization of pro‐inflammatory M1‐type macrophages, in turn stimulating the proliferation and cytokine production of CD4 + and CD8 + T cells 93 ; and by increasing infiltration of various effector immune cells and APCs in both local and distant tumors and decreasing M2‐type macrophages in the spleen 94,95 …”

Section: Combination Therapiesmentioning

confidence: 99%

Programmed cell death‐1 blockade therapy in melanoma: Resistance mechanisms and combination strategies

Zou

Yaguchi

2023

Experimental Dermatology

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Melanoma is a highly aggressive tumor derived from melanocytes. In recent years, the incidence and mortality of melanoma have gradually increased, seriously threatening human health. Classic treatments like surgery, chemotherapy, and radiotherapy show very limited efficacy. Due to the high immunogenicity of melanoma cells, immune checkpoint inhibitors have received considerable attention as melanoma treatments.One such therapy is blockade of programmed cell death-1 (PD-1), which is one of the most important negative immune regulators and is mainly expressed on activated T cells. Disruption of the interactions between PD-1 and its ligands, programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2) rejuvenates exhausted T cells and enhances antitumor immunity. Although PD-1 blockade therapy is widely used in melanoma, a substantial proportion of patients still show no response or short durations of remission. Recent researches have focused on revealing the underlying mechanisms for resistance to this treatment and improving its efficacy through combination therapy. Here, we will introduce the resistance mechanisms associated with PD-1 blockade therapy in melanoma and review the combination therapies available.

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Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma

Cited by 29 publications

References 39 publications

Data-driven analysis to identify prognostic immune-related biomarkers in BRAF mutated cutaneous melanoma microenvironment

Data-driven analysis to identify prognostic immune-related biomarkers in BRAF mutated cutaneous melanoma microenvironment

Bioinformatics analysis identifies PSMB8 as a key gene in the cutaneous malignant melanoma tumor microenvironment

Programmed cell death‐1 blockade therapy in melanoma: Resistance mechanisms and combination strategies

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