Dataset Information

Characterization of a Myeloid Activation Signature that Correlates with Survival in Melanoma Patients.

ABSTRACT: Understanding the cellular interactions within the tumor microenvironment (TME) of melanoma paved the way for novel therapeutic modalities, such as T cell-targeted immune checkpoint inhibitors (ICI). However, only a limited fraction of patients benefits from such therapeutic modalities, highlighting the need for novel predictive and prognostic biomarkers. As myeloid cells orchestrate the tumor-specific immune response and influence the efficacy of ICI, assessing their activation state within the TME is of clinical relevance. Here, we characterized a myeloid activation (MA) signature, comprising the three genes Cxcl11, Gbp1, and Ido1, from gene expression data of human myeloid cells stimulated with poly(I:C) or cGAMP. This MA signature positively correlated to overall survival in melanoma. In addition, increased expression of the MA signature was observed in melanoma patients responding to ICI (anti-PD-1), as compared to non-responders. Furthermore, the MA signature was validated in the murine B16F10 melanoma model where it was induced and associated with decreased tumor growth upon intratumoral administration of poly(I:C) and cGAMP. Finally, we were able to visualize co-expression of the MA signature genes in myeloid cells of human melanoma tissues using RNAscope in situ hybridization. In conclusion, the MA signature indicates the activation state of myeloid cells and represents a prognostic biomarker for the overall survival in melanoma patients.

SUBMITTER: Kremenovic M

PROVIDER: S-EPMC7352688 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Characterization of a Myeloid Activation Signature that Correlates with Survival in Melanoma Patients.

Kremenovic Mirela M Rombini Nives N Chan Alfred A AA Gruber Thomas T Bäriswyl Lukas L Lee Delphine J DJ Schenk Mirjam M

Cancers 20200531 6

Understanding the cellular interactions within the tumor microenvironment (TME) of melanoma paved the way for novel therapeutic modalities, such as T cell-targeted immune checkpoint inhibitors (ICI). However, only a limited fraction of patients benefits from such therapeutic modalities, highlighting the need for novel predictive and prognostic biomarkers. As myeloid cells orchestrate the tumor-specific immune response and influence the efficacy of ICI, assessing their activation state within the ...[more]

PMID: 32486450

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Project description:BackgroundReports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup.MethodsMonocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II-restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients.ResultsVaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses - notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination.ConclusionsLong-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations.Trial registrationClinicalTrials.gov NCT00053391.FundingEuropean Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).

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Dataset Information

Characterization of a Myeloid Activation Signature that Correlates with Survival in Melanoma Patients.

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Characterization of a Myeloid Activation Signature that Correlates with Survival in Melanoma Patients.

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