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1484 An interplay between innate/adaptive/humoral immunity leads to increased immunogenicity of melanoma vs. non-melanoma derived brain metastases
  1. Alberto Mendoza Valderrey1,
  2. Daria M Kessler1,
  3. Douglas A Hanes2,
  4. Ludmila Danilova3,
  5. Ethan Dettmann1,
  6. Kai Rau1,
  7. Yueqin Quan1,
  8. Stacey Stern1,
  9. Russell C Rockne4,
  10. Daniel F Kelly5,
  11. Garni Barkhoudarian5,
  12. Kim Margolin2,
  13. Steven E Kolker6 and
  14. Maria L Ascierto1
  1. 1Saint Johns Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA, USA
  2. 2Providence Research Network, Portland, OR, USA
  3. 3School of Medicine at Johns Hopkins, Baltimore, MD, USA
  4. 4Beckman Research Institute, City of Hope, Duarte, CA, USA
  5. 5Pacific Neuroscience Institute, Santa Monica, CA, USA
  6. 6Providence Saint John’s Health Center, Santa Monica, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Brain metastases (BrMs) are a devastating complication of solid tumors. Despite improvements in tumor detection and local treatment as well as the introduction of new therapies including immune checkpoint blockade (ICB) and targeted therapies, the clinical benefit is observed only for a subset of BrMs patients.1–3 A better understanding of this disease is needed to develop more effective patient selection strategies and therapeutics.

Methods In this study, multidisciplinary molecular and proteomic approaches were applied on to the peripheral blood and tumor tissues derived from primary lesions and BrMs from patients with melanoma, lung, breast, and renal cancer to evaluate in depth the tumor immune portrait behind BrMs biology.

Results The tumor microenvironment (TME) of melanoma brain metastasis (MBM) appeared to be less immunogenic when compared to the TME of primary melanoma (PM), based on less infiltration of NK and NKT cells. However, higher infiltration of CD8+, antigen presenting cells, and B cells was observed in MBM when compared to BrMs derived from other solid tumors (non-MBM). Conversely, increased infiltration of Tregs and neutrophils was found in non-MBM compared with MBM. Interestingly, the presence of immature early tertiary lymphoid structures (TLS), as another hallmark of the TME of MBM, was supported by molecular and proteomic evaluations. Furthermore, proteomic analysis revealed higher infiltration of CD8+ and CD20+ cells in MBM to be associated with longer overall survival (OS). Curiously, the presence of immature early TLS structures in a MBM patient with longer OS compared to a MBM case with lower OS also emphasizes the potential influence of TLS formation in MBM patient survival and/or response to immunotherapy. These observations suggest that presence of TLS may have a strong association or even play a functional role in the immune control of MBM.

Conclusions Taken together these results suggest that the TME of BrMs plays a pivotal role in the pathogenesis and therapeutic resistance of BrMs derived from different solid tumors.

Acknowledgements The authors thank patients, their families, the Rosalie and Harold Rae Brown Family Foundation and the Borstein Family Foundation for their support.


  1. Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, Khushalani NI, Lewis K, Lao CD, Postow MA. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. New England Journal of Medicine 2018; 379 :722–730.

  2. Tawbi HA, Forsyth PA, Hodi FS, Algazi AP, Hamid O, Lao CD, Moschos SJ, Atkins MB, Lewis K, Postow MA. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. The Lancet Oncology 2021; 22 :1692–1704.

  3. Goldberg SB, Schalper KA, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, Wilson FH, Omay SB, James BY. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. The Lancet Oncology 2020; 21 :655–663.

Ethics Approval Samples were procured under studies approved by Providence Saint Joseph Health Institutional Review Board or Western Copernicus Group Institutional Review Board. All specimens evaluated were derived from consenting patients.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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