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. 2024 Jun 5.
doi: 10.1158/1078-0432.CCR-23-3932. Online ahead of print.

Spatially informed gene signatures for response to immunotherapy in melanoma

Thazin N Aung  1 , Jonathan Warrell  2 , Sandra Martinez-Morilla  1 , Niki Gavrielatou  3 , Ioannis Vathiotis  4 , Vesal Yaghoobi  3 , Harriet M Kluger  3 , Mark Gerstein  5 , David L Rimm  3
Affiliations

Spatially informed gene signatures for response to immunotherapy in melanoma

Thazin N Aung et al. Clin Cancer Res. .

Abstract

Purpose: We aim to improve the prediction of response or resistance to immunotherapies in melanoma patients. This goal is based on the hypothesis that current gene signatures predicting immunotherapy outcomes show only modest accuracy due to the lack of spatial information about cellular functions and molecular processes within tumors and their microenvironment.

Experimental design: We collected gene expression data spatially from three cellular compartments defined by CD68+macrophages, CD45+leukocytes and S100B+tumor cells in 55-immunotherapy-treated melanoma specimens using Digital Spatial Profiling-Whole Transcriptome Atlas (DSP-WTA). We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification.

Results: We achieved robust performance of compartment-specific signatures in predicting the outcome to ICI in the discovery cohort. Of the three signatures, S100B signature showed the best performance in the validation cohort (N=45). We also compared our compartment-specific signatures with published bulk signatures and found the S100B tumor spatial signature outperformed previous signatures. Within the 8-gene S100B signature, 5 genes (PSMB8, TAX1BP3, NOTCH3, LCP2, NQO1) with positive coefficients predict the response and 3 genes (KMT2C, OVCA2, MGRN1) with negative coefficients predict the resistance to treatment.

Conclusion: We conclude that the spatially defined compartment signatures utilize tumor and TME-specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical assessment.

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