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

Mirela Kremenovic,Mirjam Schenk,Nives Rombini,Thomas Gruber,Alfred A Chan,Delphine J Lee,Lukas Bäriswyl

doi:10.3390/cancers12061431

Mirela Kremenovic, Mirjam Schenk + Show 5 more

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https://doi.org/10.3390/cancers12061431

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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.

Highlights

Recent clinical success using immune checkpoint inhibitors (ICI) has demonstrated the therapeutic potential of harnessing T cells to treat various cancer types, including cutaneous melanoma [1,2].only a proportion of patients exhibit durable responses to ICI and certain cancer types remain largely refractory to this line of treatment [1,3].While it is well known that cytotoxic T cells are a primary effector population in tumor-specific immune responses, the roles of myeloid cells in the tumor microenvironment (TME) are less clear and remain a major focus of investigation [4,5,6]
To define a human myeloid activation (MA) gene signature, peripheral blood-derived dendritic cells (DC) and CD14+ monocytes were isolated from healthy individuals and stimulated with poly(I:C)
Further analysis revealed ten differentially expressed genes (DEG) that were shared between myeloid cells stimulated with either poly(I:C) or cGAMP (Table 1)

Summary

Introduction

While it is well known that cytotoxic T cells are a primary effector population in tumor-specific immune responses, the roles of myeloid cells in the tumor microenvironment (TME) are less clear and remain a major focus of investigation [4,5,6]. Tumor-associated myeloid cells represent a vast majority of leukocytes in most tumors and regulate tumor-specific immune responses as well as responses to cancer therapies [5]. Dendritic cells (DC) and tumor-associated macrophages (TAM) are considered to be key regulators of tumor-specific immune responses due to their function in the priming and recruitment of tumor-infiltrating lymphocytes (TIL) and their ability to modulate tumor stromal and cancer cells [7,8]

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