Linking Transcriptomic and Imaging Data Defines Features of a Favorable Tumor Immune Microenvironment and Identifies a Combination Biomarker for Primary Melanoma

Abstract

◥Patients with resected stage II-III melanoma have approximately a 35% chance of death 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 þ cytotoxic T lymphocytes (CTL) to CD68 þ 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 þ macrophages, but not HLA-DR À macrophages. The HLA-DR À subset coexpressed CD163 þ CSF1R þ at higher levels than CD68 þ HLA-DR þ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic 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.

Data mining of immune-related prognostic genes in metastatic melanoma microenvironment

“…Top GO terms in the biological process included immune response, inflammatory response, signal transduction, innate immune response and adaptive immune response In addition, all the pathways that were yielded from KEGG analysis were associated with immune response. Consistent with previous studies, our findings verified that immune cells and extracellular matrix play significant roles in building the melanoma microenvironment [19][20][21]. Furthermore, we performed the overall survival analysis of 663 immune-related genes and identified that 600 genes (90.5%) were associated with better outcomes in metastatic melanoma patients.…”

Multiparameter persistent homology landscapes identify immune cell spatial patterns in tumors

“…We first analyze the spatial patterns formed by the infiltrating macrophages in the ABM using 1-PH and the PCF from spatial statistics. Both approaches provide more detailed spatial descriptors than cell counting and have been used to analyze histology data ( 11 , 12 , 34 , 37 ); we have previously validated the use of PCF to describe macrophage infiltration in human tumors by demonstrating that images grouped semiquantitatively by a pathologist share similar statistics ( 34 ). In particular, we quantify the extent to which the macrophages infiltrate the spheroid at each time point in the ABM simulations.…”

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

“…CD68 + TAM in tumor cell nests were described to be associated with a negative prognosis and recurrence in cutaneous melanoma [70]. Furthermore, the ratio of CD8 + T cells to CD68 + macrophages was shown to predict a disease specific survival in melanoma [71]. CD163 + macrophages were reported to accumulate in the TME of melanoma patients resistant to ICI therapy and to play a role in the maintenance of the immunosuppression.…”