RT Journal Article SR Electronic T1 Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e004884 DO 10.1136/jitc-2022-004884 VO 10 IS 9 A1 Jordan W Conway A1 Robert V Rawson A1 Serigne Lo A1 Tasnia Ahmed A1 Ismael A Vergara A1 Tuba N Gide A1 Grace Heloise Attrill A1 Matteo S Carlino A1 Robyn P M Saw A1 John F Thompson A1 Andrew J Spillane A1 Kerwin F Shannon A1 Brindha Shivalingam A1 Alexander Maxwell Menzies A1 James S Wilmott A1 Georgina V Long A1 Richard A Scolyer A1 Ines Pires da Silva YR 2022 UL http://jitc.bmj.com/content/10/9/e004884.abstract AB Background The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases.Methods We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV melanoma with a solitary site of organ metastasis. In an independent cohort we analyzed and compared immune cell densities, subpopulations and spatial distribution in tissue from liver, lung, brain, LN or subcut sites from 130 patients with stage IV melanoma.Results Patients with only liver, brain or bone metastases had shorter OS compared to those with lung, LN or subcutaneous and soft tissue metastases. Liver and brain metastases had significantly lower T-cell infiltration than lung (p=0.0116 and p=0.0252, respectively) and LN metastases (p=0.0116 and p=0.0252, respectively). T cells were further away from melanoma cells in liver than lung metastases (p=0.0335). Liver metastases displayed unique T-cell profiles, with a significantly lower proportion of programmed cell death protein-1+ T cells compared to all other anatomical sites (p<0.05), and a higher proportion of TIM-3+ T cells compared to LN (p=0.0004), subcut (p=0.0082) and brain (p=0.0128) metastases. Brain metastases had a lower macrophage density than subcut (p=0.0105), liver (p=0.0095) and lung (p<0.0001) metastases. Lung metastases had the highest proportion of programmed death ligand-1+ macrophages of the total macrophage population, significantly higher than brain (p<0.0001) and liver metastases (p=0.0392).Conclusions Liver and brain melanoma metastases have a significantly reduced immune infiltrate than lung, subcut and LN metastases, which may account for poorer prognosis and reduced immunotherapy response rates in patients with liver or brain metastases. Increased TIM-3 expression in liver metastases suggests TIM-3 inhibitor therapy as a potential therapeutic opportunity to improve patient outcomes.All data relevant to the study are included in the article or uploaded as supplementary information.