The expression and significance of efferocytosis and immune checkpoint related molecules in pancancer samples and the correlation of their expression with anticancer drug sensitivity

Abstract

Background: The efferocytosis-related molecules have been considered to be correlated with the resistance to cancer chemotherapy. The aim of this study was to investigate the expression and significance of efferocytosis-related molecules in cancers and the correlation of their expression with anticancer drug sensitivity, and provide new potential targets and treatment options for cancers.Methods: We investigated the differential expression of 15 efferocytosis-related molecules (Axl, Tyro3, MerTK, CX3CL1, Tim-4, BAI1, Stab2, Gas6, IDO1, Rac1, MFGE8, ICAM-1, CD47, CD31, and PD-L1) and other 12 common immune checkpoint-related molecules in tumor and normal tissues, the correlation between their expression and various clinicopathological features in 16 types of cancers using publicly available pancancer datasets in The Cancer Genome Atlas. We also analyzed the correlation of the expression of efferocytosis and immune checkpoint related molecules with 126 types of anticancer drugs sensitivity using drug-RNA-seq data.Results: There is a panel of circulating molecules among the 27 molecules. Based on the results of differential expression and correlation with various clinicopathological features of efferocytosis-related molecules in cancers, we identified new potential therapeutic targets for anticancer therapy, such as Axl for kidney renal clear cell carcinoma, Tyro3 for liver hepatocellular carcinoma, and IDO1 for renal papillary cell carcinoma. Except for BAI1, CD31, and MerTK, the enhanced expressions of Axl, Tyro3, Gas6, MFGE8, Stab2, Tim-4, CX3CL1, IDO1, Rac1, and PD-L1 were associated with decreased sensitivity of the cancer cells to many anti-cancer drugs; however, for other common immune checkpoint-related molecules, only enhanced expressions of PD-1, CD28, CTLA4, and HVEM were associated with decreased sensitivity of the cancer cells to a few drugs.Conclusion: The efferocytosis-related molecules were significantly associated with clinical outcomes in many types of cancers and played important roles in resistance to chemotherapy. Combination therapy targeting efferocytosis-related molecules and other immune checkpoint-related molecules is necessary to reduce resistance to chemotherapy.

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms

“…Arginine from ACs is transformed to putrescine to activate RAC1 to promote continual efferocytosis ( 45 ), and this arginine metabolism can be regulated by 3,3′-diindolylmethane ( 202 ). Indoleamine-2,3-dioxegenase1 promotes the transformation of tryptophan to kynurenine, and the latter enhances the expression of IL-10 and transforming growth factor-β ( 203 , 204 ). Additionally, AC-derived methionine transforms to S-adenosylmethionine, and the latter contributes to enhancing the expression of transforming growth factor-β via DNA methyltransferase-3A ( 205 ).…”

Combining bulk and scRNA‐seq to explore the molecular mechanisms governing the distinct efferocytosis activities of a macrophage subpopulation in PDAC

“…However, the level of efferocytosis activity exhibited by macrophages in PDAC remains uncertain. 15,16 The proposed study aims to employ single-cell sequencing technology to examine the efferocytosis activity, transcriptional regulatory networks and cellular communication mechanisms between macrophages and tumour cells in the setting of PDAC. This methodology will facilitate our comprehension of the molecular and cellular connections that underlie this particular ailment, perhaps yielding significant insights into innovative therapy options.…”

“…Recent research has demonstrated that cancers can exploit efferocytosis, a kind of cell death, to advance cancer growth and evade immune system detection. However, the level of efferocytosis activity exhibited by macrophages in PDAC remains uncertain 15,16 …”

“…However, the level of efferocytosis activity exhibited by macrophages in PDAC remains uncertain. 15 , 16 …”

Anoikis‐related genes as potential prognostic biomarkers in gastric cancer: A multilevel integrative analysis and predictive therapeutic value

“…Caspase‐8, as a member of the cysteine protease family, activates during anoikis, augments cell death, and inhibits peritoneal dissemination of human GC cells [10]. Besides, immune checkpoint expression (including Tyro3, Gas6, MFGE8, Stab2, Tim‐4, CX3CL1, IDO1, Rac1, and PD‐L1) is directed against cancer cells to avoid immune attack, and they were associated with reducing the half‐maximal drug inhibitory concentration (IC50) for multiple anti‐cancer drugs [11]. Therefore, mining immunotherapeutic biomarkers and the role of epigenetics in gene regulation further assist GC patients in formulating precise immunotherapy regimens for durable efficacy.…”