Clinical Predictors of Response to Anti-PD-1 First-Line Treatment in a Single-Centre Patient Cohort: A Real-World Study

Pietro, Francesca Di; Verkhovskaia, Sofia; Mastroeni, Simona; Carbone, Maria Luigia; Abeni, Damiano; Rocco, C. Z. Di; Samà, N.; Zappalà, Alba; Marchetti, Paolo; Galitiis, Federica De; Failla, Cristina Maria; Fortes, Cristina

doi:10.1016/j.clon.2021.09.006

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…These findings are also consistent with prior studies implicating TLR polymorphisms and signaling to support the establishment of pulmonary metastases (13,45). The results presented here are interesting to consider in light of a recent retrospective study that found respiratory diseases and elevated neutrophil:lymphocyte ratios to be associated with disease progression in patients with stage IV melanoma undergoing anti-PD-1 immunotherapy (46). Overall, these findings suggest that there is a continuum between mechanisms of adaptive resistance and HPD in patients undergoing checkpoint inhibitor immunotherapy.…”

Section: Discussionsupporting

confidence: 91%

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy

et al. 2022

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The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8 + T cell cytotoxicity and contributes to the development of adaptive resistance to anti–programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti–PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti–PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti–PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti–PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

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Section: Discussionsupporting

confidence: 91%

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy

et al. 2022

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“…Patients with poor PS have a worse outcome in terms of ORR, PFS, and OS. However, they experienced a similar safety profile, and an important portion of patients with poor PS could benefit from immunotherapy [ 52 , 191 , 192 , 193 , 194 , 195 , 196 ].…”

Section: Third Line Predictive/prognostic Factorsmentioning

confidence: 99%

“…Higher potentiality for single-cell and topographical evaluation. Performance status (PS) [52,[191][192][193][194][195][196] Medical history and clinical examination…”

Section: Introductionmentioning

confidence: 99%

Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective

Poletto,

Paruzzo,

Nepote

et al. 2023

Cancers

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The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma. Despite the impressive results associated with immune checkpoint inhibitors (ICIs), only a portion of patients obtain a response to this treatment. In this scenario, the research of predictive factors is fundamental to identify patients who may have a response and to exclude patients with a low possibility to respond. These factors can be host-associated, immune system activation-related, and tumor-related. Patient-related factors can vary from data obtained by medical history (performance status, age, sex, body mass index, concomitant medications, and comorbidities) to analysis of the gut microbiome from fecal samples. Tumor-related factors can reflect tumor burden (metastatic sites, lactate dehydrogenase, C-reactive protein, and circulating tumor DNA) or can derive from the analysis of tumor samples (driver mutations, tumor-infiltrating lymphocytes, and myeloid cells). Biomarkers evaluating the immune system activation, such as IFN-gamma gene expression profile and analysis of circulating immune cell subsets, have emerged in recent years as significantly correlated with response to ICIs. In this manuscript, we critically reviewed the most updated literature data on the landscape of predictive factors in metastatic melanoma treated with ICIs. We focus on the principal limits and potentiality of different methods, shedding light on the more promising biomarkers.

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“…In the past decade, the emergence of targeted therapy and immunotherapy has considerably improved the overall survival (OS) of melanoma patients ( Michielin et al, 2019 ). However, only half of the metastatic melanoma patients respond to checkpoint inhibitor therapy ( Di Pietro et al, 2021 ), which might attribute to subtype bias, intra-tumor heterogeneity ( Lu et al, 2021 ), low mutational load ( Budczies et al, 2018 ), phenotypic plasticity, etc. ( Valsecchi, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Construction and Validation of a 6-Ferroptosis Related Gene Signature for Prognosis and Immune Landscape Prediction in Melanoma

2022

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Ferroptosis is a newly discovered form of non-apoptotic cell death that relies on iron-mediated oxidative damage, playing a crucial role in the progression and therapy resistance of melanoma. Hence, the potential value of ferroptosis-related genes (FRGs) as a prognostic model and therapeutic target in melanoma requires further investigation. In this study, the relationship between FRGs and melanoma was revealed by analyzing the mRNA expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Synthesis (GEO). A 6-FRGs signature was constructed by Univariate, multivariate, and lasso Cox regression analyses in the TCGA cohort. The GEO database was used to validate the efficacy of the signature. The protein and mRNA expression level of the signature genes were examined in real-world melanoma tissues via immunohistochemical and quantificational real-time polymerase chain reaction (qRT-PCR). Functional enrichment analysis and immune-related analysis were conducted to identify the potential biological functions and pathways of the signature. Ten putative small molecule drugs were predicted by Connectivity Map (CMAP). As a result, a 6-FRGs signature was constructed to stratify melanoma patients into two risk groups. Compared with the low-risk group, patients in the high-risk group had a worse prognosis and a lower ImmuneScore. Immune-related pathways were enriched in the low-risk group. Immune Function and immune cell infiltration of the low-risk group were significantly higher than that of the high-risk group. The differential expression of these six FRGs in melanoma and adjacent normal tissues was confirmed. Moreover, higher expression of immune checkpoint molecules and a greater sensitivity to immunotherapy were observed in the low-risk group. Some small molecular drugs in the CMAP database hold the potential to treat melanoma. Overall, we identified a novel FRGs signature for prognostic prediction in melanoma. Based on the signature-related immune infiltration landscape found in our study, targeting the FRGs might be a therapeutic alternative for melanoma.

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Clinical Predictors of Response to Anti-PD-1 First-Line Treatment in a Single-Centre Patient Cohort: A Real-World Study

Cited by 6 publications

References 30 publications

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy

Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective

Construction and Validation of a 6-Ferroptosis Related Gene Signature for Prognosis and Immune Landscape Prediction in Melanoma

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