{"doi":"10.1002/cac2.12540","title":"Immune cell pair ratio captured by imaging mass cytometry has superior predictive value for prognosis of non‐small cell lung cancer than cell fraction and density","abstract":"Infiltrating immune cells in the tumor microenvironment (TME) play critical roles in the initiation, progression, and metastasis of cancer [1]. Previous studies have reported that the infiltration levels of various immune cell types are significantly associated with patient prognosis in different cancers [2, 3]. Specifically, in non-small cell lung cancer (NSCLC) the prognostic associations of major immune cell types have been investigated [4-6], however, some of the reported associations are inconsistent and remain debated [7]. Limited by technical issues, most studies focused on a few immune cell lineages or relied on inferred immune cell levels from computational deconvolution. To investigate the prognostic effects of all major immune cell types unbiasedly, more systematic high-quality immune cell profiling data with matched patient survival information are needed. Recently, Sorin et al. [8] used imaging mass cytometry (IMC) to characterize the immunological landscape of 416 distinct lung adenocarcinoma (LUAD) samples at single-cell resolution. The IMC images provide the counts and spatial distribution of 16 cell types with high precision in each sample. These cell types include cancer and endothelial cells, along with 14 immune cell types, including CD163+ and CD163− macrophages, CD8+, CD4+, regulatory, and other T cells, classical, non-classical, and intermediate monocytes, natural killer cells, dendritic cells, mast cells, neutrophils, and other immune cells. Additionally, the data provide patient survival and other clinical information. Using these data, we investigated the prognostic associations of the cell density (#cells/megapixel) and fractions of the 16 cell types as well as the fraction ratio between each pair of cell types (Supplementary Methods). Our results indicated that the relative abundance between cell types (fraction ratios) was more prognostic than cell fractions and densities. We calculated the densities of the 16 cell types in each patient's IMC image and applied Cox regression analysis to examine their associations with progression-free survival (PFS) after adjusting for established clinical factors including age, sex, smoking status, and tumor stage. At the significance level of P < 0.05, only the density of non-classical monocytes was found to have a significant association with worse prognosis (hazard ratio [HR] = 1.004, P = 0.040, Figure 1A). After multiple testing corrections, none of the cell types was significant (false discovery rate [FDR] > 0.05). Similar results were obtained when cell fractions among all cells were used for prognostic association analysis (Figure 1B). In addition, we conducted prognostic analysis on 14 immune cell types, focusing on their proportions among immune cells (excluding cancer and endothelial cells), yielding similar results. It has been well-known that some cell types play more immune suppressive toles in the TME, while others are more stimulatory. We therefore investigated the prognostic effect of relative abundance between different cell types. For each pair of the 16 cell types we calculated the ratio of their cell fractions (equal to the ratio of cell densities). From these ratios, we identified 28 cell pairs significantly associated with PFS (P < 0.05), adjusted for clinical factors (Figure 1C). After multiple testing corrections, 9 pairs remained significant (FDR < 0.05). As an example, the non-classical monocyte/CD4+ T cell ratio was associated with a significantly worse PFS (P < 0.001). We conducted a multivariable Cox regression model incorporating the fractions of non-classical monocytes, CD4+ T cells, their ratio, and various clinical factors. The result indicated that neither non-classical monocytes nor CD4+ T cells was significant, but the non-classical monocyte/CD4+ T cell ratio was significantly associated with a shorter PFS (Figure 1D). Similar results were obtained when overall survival (OS) was used: cell-cell ratios were more prognostic than c","journal":"Cancer Communications","year":2024,"id":470742,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9639,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":363,"name":"Chao Cheng","orcid":"0000-0002-5002-3417","position":1,"is_corresponding":false},{"id":5673,"name":"Jianrong Li","orcid":"0000-0003-2382-6270","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:05:40.740958Z","pmid":"38532538","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}