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Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma.

ABSTRACT: Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.

SUBMITTER: Reuben A

PROVIDER: S-EPMC5557036 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma.

Reuben Alexandre A Spencer Christine N CN Prieto Peter A PA Gopalakrishnan Vancheswaran V Reddy Sangeetha M SM Miller John P JP Mao Xizeng X De Macedo Mariana Petaccia MP Chen Jiong J Song Xingzhi X Jiang Hong H Chen Pei-Ling PL Beird Hannah C HC Garber Haven R HR Roh Whijae W Wani Khalida K Chen Eveline E Haymaker Cara C Forget Marie-Andrée MA Little Latasha D LD Gumbs Curtis C Thornton Rebecca L RL Hudgens Courtney W CW Chen Wei-Shen WS Austin-Breneman Jacob J Sloane Robert Szczepaniak RS Nezi Luigi L Cogdill Alexandria P AP Bernatchez Chantale C Roszik Jason J Hwu Patrick P Woodman Scott E SE Chin Lynda L Tawbi Hussein H Davies Michael A MA Gershenwald Jeffrey E JE Amaria Rodabe N RN Glitza Isabella C IC Diab Adi A Patel Sapna P SP Hu Jianhua J Lee Jeffrey E JE Grimm Elizabeth A EA Tetzlaff Michael T MT Lazar Alexander J AJ Wistuba Ignacio I II Clise-Dwyer Karen K Carter Brett W BW Zhang Jianhua J Futreal P Andrew PA Sharma Padmanee P Allison James P JP Cooper Zachary A ZA Wargo Jennifer A JA

NPJ genomic medicine 20170407

Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (<i>n</i> = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune ...[more]

PMID: 28819565

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Project description:BackgroundMacrophage-based cell therapies have shown modest success in clinical trials, which can be attributed to their phenotypic plasticity, where transplanted macrophages get reprogrammed towards a pro-tumor phenotype. In most tumor types, including melanoma, the balance between antitumor M1-like and tumor-promoting M2-like macrophages is critical in defining the local immune response with a higher M1/M2 ratio favoring antitumor immunity. Therefore, designing novel strategies to increase the M1/M2 ratio in the TME has high clinical significance and benefits macrophage-based cell therapies.MethodsIn this study, we reprogrammed antitumor and proinflammatory macrophages ex-vivo with HDAC6 inhibitors (HDAC6i). We administered the reprogrammed macrophages intratumorally as an adoptive cell therapy (ACT) in the syngeneic SM1 murine melanoma model and patient-derived xenograft bearing NSG-SGM3 humanized mouse models. We phenotyped the tumor-infiltrated immune cells by flow cytometry and histological analysis of tumor sections for macrophage markers. We performed bulk RNA-seq profiling of murine bone marrow-derived macrophages treated with vehicle or HDAC6i and single-cell RNA-seq profiling of SM1 tumor-infiltrated immune cells to determine the effect of intratumor macrophage ACT on the tumor microenvironment (TME). We further analyzed the single-cell data to identify key cell-cell interactions and trajectory analysis to determine the fate of tumor-associated macrophages post-ACT.ResultsMacrophage ACT resulted in diminished tumor growth in both mouse models. We also demonstrated that HDAC6 inhibition in macrophages suppressed the polarization toward tumor-promoting phenotype by attenuating STAT3-mediated M2 reprogramming. Two weeks post-transplantation, ACT macrophages were viable, and inhibition of HDAC6 rendered intratumor transplanted M1 macrophages resistant to repolarization towards protumor M2 phenotype in-vivo. Further characterization of tumors by flow cytometry, single-cell transcriptomics, and single-cell secretome analyses revealed a significant enrichment of antitumor M1-like macrophages, resulting in increased M1/M2 ratio and infiltration of CD8 effector T-cells. Computational analysis of single-cell RNA-seq data for cell-cell interactions and trajectory analyses indicated activation of monocytes and T-cells in the TME.ConclusionsIn summary, for the first time, we demonstrated the potential of reprogramming macrophages ex-vivo with HDAC6 inhibitors as a viable macrophage cell therapy to treat solid tumors.

Dataset Information

Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma.

Publications

Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma.

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