Abstract
BackgroundTumor infiltrating myeloid (TIM) cells constitute a vital element of the tumor microenvironment. The cell-type heterogeneity of TIM has yet to be fully investigated.MethodsWe 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.ResultsTwo 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.ConclusionAltogether, 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.
Highlights
Lung adenocarcinomas (LUADs) account for over 40% of lung cancers and represent its most leading and prevalent histological subtype
We reveal the relationship between MSC subtype and immune checkpoint blockade (ICB) therapy and identify three Tumor infiltrating myeloid (TIM) subtypes that might contribute to the ICB response
In the The Cancer Genome Atlas (TCGA) LUAD cohort, we introduced the tumor immune dysfunction and exclusion (TIDE) algorithm to explore the relationship between the MSC subtype and ICB response [35]
Summary
Lung adenocarcinomas (LUADs) account for over 40% of lung cancers and represent its most leading and prevalent histological subtype. Despite an improvement in therapeutic strategies, the rates of objective clinical responses remain low, with only 17.4% lung cancer patients surviving more than 5 years beyond diagnosis [1]. The dynamic tumor immune microenvironment plays an important role in tumor progression and metastasis [2, 3]. Tumor-infiltrating T lymphocytes are recognized as the key components of the tumor microenvironment (TME). Therapeutic strategies for targeting these cells are being actively developed and have demonstrated remarkable therapeutic effects [4]. While current immunotherapies targeting T lymphocytes benefit only few patients [5], it is important to unravel the exact cellular functions of the remaining cell types within the TME that may be involved in tumor progression. 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
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