Immunological and clinical immunotherapy implications of NLRP3 mutations in melanoma

Wang, Qinghua; Lyu, Juncheng; Zhang, Wenjing; Shi, Fuyan; Ren, Yudong; Mao, Qian; Liu, Yujie; Li, Yuting; Wang, Shuzhen

doi:10.18632/aging.203678

Cited by 7 publications

(3 citation statements)

References 46 publications

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“…NLRP3 has previously been identified as a double-edged sword in oncogenesis and influences the immune response by regulating host immunity. Melanoma patients with an NLRP3 mutation were found to exhibit increased infiltration of immune response cells, which was associated with better clinical efficacy [ 69 ]. In contrast, NLRP3 signaling in TAMs in pancreatic cancer drives macrophage-induced immunosuppression, thereby inhibiting CD8+ T-cell activation [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

Luo,

Li,

et al. 2023

Cell Mol Immunol

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The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from “cold” to “hot” and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

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Section: Discussionmentioning

confidence: 99%

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

Luo,

Li,

et al. 2023

Cell Mol Immunol

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“…Therefore, easier surrogates are necessary for such clinical settings. Recent research has shown that mutations in single genes, such as POLE [ 9 ], NLRP3 [ 55 ], COL3A1 [ 12 ], and PTPRT [ 54 ] could predict tumor TMB and immunotherapeutic response. In this study, HSPG2 mutations were also determined to link with an elevated mutational burden and a preferable ICI efficacy in melanoma and NSCLC, which indicates that HSPG2 mutations may be a possible indicator for TMB and cancer immune treatment response.…”

Section: Discussionmentioning

confidence: 99%

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

Zhang

Lin

Shi

et al. 2022

Cancers

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Immune checkpoint inhibitors (ICIs) markedly promote the survival outcome of advanced melanoma and non-small cell lung cancer (NSCLC). Clinically, favorable ICI treatment efficacy is noticed only in a smaller proportion of patients. Heparan sulfate proteoglycan 2 (HSPG2) frequently mutates in both tumors. Herein, we aim to investigate the immunotherapeutic and immunological roles of HSPG2 mutations in melanoma and NSCLC. A total of 631 melanoma samples and 109 NSCLC samples with both somatic mutational profiles and clinical immunotherapy data were curated. In addition, by using The Cancer Genome Atlas data, genomic and immunological traits behind HSPG2 mutations were elucidated. Melanoma patients with HSPG2 mutations had a markedly extended ICI outcome than other patients. An association between HSPG2 mutations and the improved outcome was further confirmed in NSCLC. In addition, an elevated ICI response rate was presented in HSPG2-mutated NSCLC patients (81.8% vs. 29.7%, p = 0.002). Subsequent analyses revealed that HSPG2-mutated patients had a favorable abundance of response immunocytes, an inferior abundance of suppression immunocytes, enhanced mutational burden, and interferon response-relevant signaling pathways. We uncovered that HSPG2 mutations were predictive of a better ICI response and associated with preferable immunogenicity, which may be considered as a genomic determinant to customize biotherapy strategies.

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“…The capability of the NLRP3 inflammasome to promote an immune response provides the potential to predict the response to immunotherapy. In melanoma, the mutational burden of the NLRP3 gene could provide useful data about the response to immunotherapy [95]. Unfortunately, despite the necessity of detecting and implementing into clinical practice new biomarkers for HCC [77], the evidence regarding the role of NLRP3 as a biomarker in HCC is limited.…”

Section: The Nlrp3 As Biomarkermentioning

confidence: 99%

The Role of the NLRP3 Inflammasome in HCC Carcinogenesis and Treatment: Harnessing Innate Immunity

Papadakos

Dedes

Kouroumalis

et al. 2022

Cancers

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The HCC constitutes one of the most frequent cancers, with a non-decreasing trend in disease mortality despite advances in systemic therapy and surgery. This trend is fueled by the rise of an obesity wave which is prominent the Western populations and has reshaped the etiologic landscape of HCC. Interest in the nucleotide-binding domain leucine-rich repeat containing (NLR) family member NLRP3 has recently been revived since it would appear that, by generating inflammasomes, it participates in several physiologic processes and its dysfunction leads to disease. The NLRP3 inflammasome has been studied in depth, and its influence in HCC pathogenesis has been extensively documented during the past quinquennial. Since inflammation comprises a major regulator of carcinogenesis, it is of paramount importance an attempt to evaluate the contribution of the NLRP3 inflammasome to the generation and management of HCC. The aim of this review was to examine the literature in order to determine the impact of the NLRP3 inflammasome on, and present a hypothesis about its input in, HCC.

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Immunological and clinical immunotherapy implications of NLRP3 mutations in melanoma

Cited by 7 publications

References 46 publications

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

The Role of the NLRP3 Inflammasome in HCC Carcinogenesis and Treatment: Harnessing Innate Immunity

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