Microdissection of the Bulk Transcriptome at Single-Cell Resolution Reveals Clinical Significance and Myeloid Cells Heterogeneity in Lung Adenocarcinoma

Abstract

Background: Tumor infiltrating myeloid (TIM) cells constitute a vital element of the tumor microenvironment. The cell-type heterogeneity of TIM has yet to be fully investigated. Methods: We used a time saving approach to generate a single-cell reference matrix, allowing quantification of cell-type proportions and cell-type-specific gene abundances in bulk RNA-seq data. Results: Two distinct clusters, MSC1 and MSC2 (MSC subtype) were newly identified in lung adenocarcinoma (LUAD) patients, both significantly associated with overall survival and immune blockade therapy responses. Twenty myeloid cell types were detected. Thirteen of these had distinct enrichment patterns between MSC1 and MSC2. LAMP3+ dendritic cells, being a mature and transportable subtype of dendritic cell that may migrate to lymph nodes, were noted as associated with non-responsiveness to immunotargeted therapy. High infiltration level of IFIT3+ neutrophils was strongly related to the response to immune-targeted therapy and was seen to activate CD8+ T cells, partly through inflammasome activation. The infiltration levels of TIMP1+ macrophages and S100A8+ neutrophils were both significantly associated with poor prognosis. TIMP1+ macrophages were noted to recruit S100A8+ neutrophils via the CXCL5–CXCR2 axes and promote LUAD progression. Conclusion: Altogether, we performed virtual microdissection of the bulk transcriptome at single-cell resolution and provided a promising TIM infiltration landscape that may shed new light on the development of immune therapy.