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

Gino K In; Jennifer R Ribeiro; Jun Yin; Joanne Xiu; Matias A Bustos; Fumito Ito; Frances Chow; Gabriel Zada; Lindsay Hwang; April K S Salama; Soo J Park; Justin C Moser; Sourat Darabi; Evidio Domingo-Musibay; Maria L Ascierto; Kim Margolin; Jose Lutzky; Geoffrey T Gibney; Michael B Atkins; Benjamin Izar; Dave S B Hoon; Ari M VanderWalde

doi:10.1038/s41698-023-00471-z

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

NPJ Precis Oncol. 2023 Nov 14;7(1):120. doi: 10.1038/s41698-023-00471-z.

Authors

Gino K In¹, Jennifer R Ribeiro², Jun Yin², Joanne Xiu², Matias A Bustos³, Fumito Ito⁴, Frances Chow^{5

6}, Gabriel Zada⁶, Lindsay Hwang^{7

8}, April K S Salama⁹, Soo J Park¹⁰, Justin C Moser¹¹, Sourat Darabi¹², Evidio Domingo-Musibay¹³, Maria L Ascierto¹⁴, Kim Margolin¹⁵, Jose Lutzky¹⁶, Geoffrey T Gibney¹⁷, Michael B Atkins¹⁸, Benjamin Izar¹⁹, Dave S B Hoon³, Ari M VanderWalde^{20

21}

Affiliations

¹ Division of Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Gino.In@med.usc.edu.
² Caris Life Sciences, Phoenix, AZ, USA.
³ Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.
⁴ Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ Department of Neurology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Neurological Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ LAC+USC Medical Center, Los Angeles, CA, USA.
⁸ Department of Radiation Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC, USA.
¹⁰ Division of Hematology/Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹¹ HonorHealth Research and Innovation Institute, Scottsdale, AZ, USA.
¹² Hoag Family Cancer Institute, Hoag Hospital, Newport Beach, CA, USA.
¹³ Department of Medicine, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.
¹⁴ Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Department of Translational Immunology, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.
¹⁵ Department of Medical Oncology, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.
¹⁶ Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.
¹⁷ Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA.
¹⁸ Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA.
¹⁹ Columbia University, Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
²⁰ Caris Life Sciences, Irving, TX, USA.
²¹ West Cancer Center and Research Institute, 514 Chickasawba St., Blytheville, Arkansas, 72315, USA.

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.

Abstract

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