TY - JOUR
T1 - Linking transcriptomic and imaging data defines features of a favorable tumor immune microenvironment and identifies a combination biomarker for primary melanoma
AU - Gartrell-Corrado, Robyn D.
AU - Chen, Andrew X.
AU - Rizk, Emanuelle M.
AU - Marks, Douglas K.
AU - Bogardus, Margaret H.
AU - Hart, Thomas D.
AU - Silverman, Andrew M.
AU - Bayan, Claire Audrey Y.
AU - Finkel, Grace G.
AU - Barker, Luke W.
AU - Komatsubara, Kimberly M.
AU - Carvajal, Richard D.
AU - Horst, Basil A.
AU - Chang, Rui
AU - Monod, Anthea
AU - Rabadan, Raul
AU - Saenger, Yvonne M.
N1 - Publisher Copyright: © 2020 American Association for Cancer Research.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Patients with resected stage II-III melanoma have approximately a 35% chance ofdeath from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an IFN-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTL) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary with metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR macrophages. The HLA-DR subset coexpressed CD163 CSF1R at higher levels than CD68 HLA-DR macrophages, consistent with an M2 phenotype. Finally, combined tran-scriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy. Significance: These findings provide a deeper understanding of the tumor immune microenvironment by combining multiple modalities to stratify patients into risk groups, a critical step to improving the management of patients with melanoma.
AB - Patients with resected stage II-III melanoma have approximately a 35% chance ofdeath from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an IFN-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTL) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary with metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR macrophages. The HLA-DR subset coexpressed CD163 CSF1R at higher levels than CD68 HLA-DR macrophages, consistent with an M2 phenotype. Finally, combined tran-scriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy. Significance: These findings provide a deeper understanding of the tumor immune microenvironment by combining multiple modalities to stratify patients into risk groups, a critical step to improving the management of patients with melanoma.
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U2 - 10.1158/0008-5472.CAN-19-2039
DO - 10.1158/0008-5472.CAN-19-2039
M3 - Article
C2 - 31948941
SN - 0008-5472
VL - 80
SP - 1078
EP - 1087
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -