Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts

Abstract

Multiple soluble factors including proteins (in particular chemokines), non-proteinaceous factors released by dead cells, as well as receptors for such factors (in particular chemokine receptors, formyl peptide receptors and purinergic receptors), influence the recruitment of distinct cell subsets into the tumor microenvironment. We performed an extensive bioinformatic analysis on tumor specimens from 5953 cancer patients to correlate the mRNA expression levels of chemotactic factors/receptors with the density of immune cell types infiltrating the malignant lesions. This meta-analysis, which included specimens from breast, colorectal, lung, ovary and head and neck carcinomas as well as melanomas, revealed that a subset of chemotactic factors/receptors exhibited a positive and reproducible correlation with several infiltrating cell types across various solid cancers, revealing a universal pattern of association. Hence, this meta-analysis distinguishes between homogeneous associations that occur across different cancer types and heterogeneous correlations, that are specific of one organ. Importantly, in four out of five breast cancer cohorts for which clinical data were available, the levels of expression of chemotactic factors/receptors that exhibited universal (rather than organ-specific) positive correlations with the immune infiltrate had a positive impact on the response to neoadjuvant chemotherapy. These results support the notion that general (rather than organ-specific) rules governing the recruitment of immune cells into the tumor bed are particularly important in determining local immunosurveillance and response to therapy.

Immune mediator expression signatures are associated with improved outcome in ovarian carcinoma

“…Consistent with our findings, the CXCL-9/CXCL-10/ CXCL-11-CXCR3 axis has been reported to lead to enhanced tumor growth restriction by recruitment of CD8 + T cells (CTLs), NK cells and macrophages. [27][28][29][30][31] In mouse models, CXCL-11, as an adjuvant to oncolytic virus-based treatments, could significantly enhance their anti-tumor efficacy, 29 and CXCL-11-Fc fusions enhanced recruitment of antigen-specific CD8 + T cells. 32 Furthermore, secretion of these three mediators by monocytes, endothelial cells, fibroblasts and cancer cells was enhanced through transcriptional activation of STAT1 and NFκB, caused by IFNγ and TNFα working in synergy.…”

Serum Chemokine-release Profiles in AML-patients Might Contribute to Predict the Clinical Course of the Disease

“…CXCL9 and CXCL10 play a critical role in the recruitment of T and NK cells into tumors of various origins and it has been demonstrated that blockade of either them or their receptor CXCR3, impairs recruitment of adoptively transferred T cells into melanoma tumors (Chheda et al 2016;Mikucki et al 2015;Stoll et al 2018).…”

Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization

“…Breast cancer [19,75] TAMs [47,64,75] Cervical cancer [19] Lung cancer [19] Multiple myeloma [19] Osteosarcoma [76] Pancreatic cancer [19] Prostate cancer [19] CCR6 CCL20…”

“…A comprehensive meta-analysis of more than 5000 tumor specimens from patients with breast, colorectal, lung, ovary, head and neck carcinomas, as well as melanomas, recently revealed that a universal pattern of correlation exists between the relative abundance of distinct leukocyte subsets infiltrating the tumors and the expression of individual chemokines-receptors, regardless of the cancer type and localization [75]. Indeed, CCR1, CCR2, CCR5, CXCR4, CCL18, CCL19, CCL21, and CXCL12 expression has been identified to positively correlate with immune infiltration of breast and colorectal carcinomas, non-small cell lung cancer and melanomas [75].…”

“…The homeostatic chemokines CXCL12 and CCL21 have been reported to be crucial players in supporting all the stages of the metastatic process, as they physiologically dictate cell positioning throughout the body, both during tissue development and immune response [181]. Importantly, the aforementioned meta-analysis revealed that tumor infiltration of T cells and neutrophils are mutually exclusive, as neutrophil recruitment inversely correlates with CXCL9, CXCL10 and CXCL11, which conversely promote lymphocyte accumulation [75].…”