Dataset Information

Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases.

ABSTRACT: Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.

SUBMITTER: In GK

PROVIDER: S-EPMC10646102 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases.

In Gino K GK Ribeiro Jennifer R JR Yin Jun J Xiu Joanne J Bustos Matias A MA Ito Fumito F Chow Frances F Zada Gabriel G Hwang Lindsay L Salama April K S AKS Park Soo J SJ Moser Justin C JC Darabi Sourat S Domingo-Musibay Evidio E Ascierto Maria L ML Margolin Kim K Lutzky Jose J Gibney Geoffrey T GT Atkins Michael B MB Izar Benjamin B Hoon Dave S B DSB VanderWalde Ari M AM

NPJ precision oncology 20231114 1

Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which ...[more]

PMID: 37964004

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Project description:BackgroundThe bone marrow is the place of hematopoiesis with a microenvironment that supports lifelong maintenance of stem cells and high proliferation. It is not surprising that this environment is also favourable for malignant cells emerging in the bone marrow or metastasizing to it. While the cellular composition of the bone marrow microenvironment has been extensively studied, the extracellular matrix and interstitial fluid components have received little attention. Since the sinusoids connect the bone marrow interstitial fluid to the circulation, it is often considered to have the same composition as peripheral blood plasma. Stark differences in the cellular composition of the bone marrow and peripheral blood with different secretory capacities would however suggest profound differences.MethodsIn this study we set out to better define if and how the bone marrow interstitial fluid (BMIF) compares to the peripheral blood plasma (PBP) and how both are remodeled during chemotherapy. We applied a multi-omic strategy to quantify the metabolite, lipid and protein components as well as the proteolytic modification of proteins to gain a comprehensive understanding of the two compartments.ResultsWe found that the bone marrow interstitial fluid is clearly distinct from peripheral blood plasma, both during active pediatric acute lymphoblastic leukemia and following induction chemotherapy. Either compartment was shaped differently by active leukemia, with the bone marrow interstitial fluid being rich in extracellular vesicle components and showing protease dysregulation while the peripheral blood plasma showed elevation of immune regulatory proteins. Following chemotherapy, the BMIF showed signs of cellular remodeling and impaired innate immune activation while the peripheral blood plasma was characterized by restored lipid homeostasis.ConclusionThis study provides a comprehensive examination of the fluid portion of the acute lymphoblastic leukemia microenvironment and finds the contribution of either microenvironment to tumourigenesis.

Project description:Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant (SOT) recipients, who have atypical but poorly characterized immune responses to SARS-CoV-2 infection. We sought to understand and the host immunologic and microbial features of COVID-19 in SOT recipients by leveraging a prospective multicenter cohort of 1164 hospitalized patients. Using multi-omic immuoprofiling, we studied 86 SOT recipients in this cohort, who were age- and sex-matched 2:1 with 172 non-SOT controls. PBMC and nasal transcriptional profiling unexpectedly demonstrated upregulation of innate immune pathways related to interferon (IFN) and Toll-like receptor signaling, and complement activation, in SOT recipients. Longitudinal analyses across the first 30-days post-hospitalization demonstrated persistent upregulation of these innate immunity pathways in SOT recipients. The levels of several proinflammatory serum chemokines, such as CX3CL1 and KITLG, were also higher in SOT recipients at the time of hospitalization, although IFN-gamma levels were lower. We observed differential dynamics of CXCL11, which remained persistently elevated in SOT recipients over the course of hospitalization. Nasal microbiome alpha diversity was higher in SOT recipients versus controls, but no differences in taxonomic abundance beyond SARS-CoV-2 were observed. SOT recipients had higher nasal SARS-CoV-2 viral loads and impaired viral clearance compared to controls. Antibody analysis demonstrated lower anti-SARS-CoV-2 spike IgG levels in SOT recipients upon hospitalization, but no distinctions over time compared to controls. Mass cytometry demonstrated marked differences in blood immune cell populations, with SOT recipients exhibiting decreased plasmablasts and transitional B cells, and increased senescent T cells. Severe disease in SOT recipients was characterized by a less robust induction of inflammatory chemokines, such as IL-6 and CCL7, and a more subtle proinflammatory transcriptional response in the blood and airway. Together, our study reveals distinct immune features and altered viral dynamics in SOT recipients compared to non-SOT controls. We unexpectedly find that SOT recipients exhibit an augmented, predominantly innate immune response in both the blood and upper respiratory tract that remains relatively stable across disease severity, in contrast to non-SOT controls. These findings may relate to the paradoxical observation that SOT recipients have similar COVID-19 mortality rates versus the general population, despite being more susceptible to SARS-CoV-2 infection, remaining infectious longer, and having higher rates of hospitalization. In summary, we find that COVID-19 in SOT recipients is characterized by a biologically distinct immune state, suggesting the potential for unique prognostic biomarkers and therapeutic approaches in this vulnerable population.

Dataset Information

Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases.

Publications

Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases.

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