Serum macrophage-derived chemokine/CCL22 levels are associated with glioma risk, CD4 T cell lymphopenia and survival time

Abstract

Defects in antigen presenting cell function have been implicated in glioma immunosuppression. We measured peripheral CCL22, a dendritic cell/macrophage derived T cell trafficking chemokine, in sera from 1,208 glioma cases and 976 controls to assess whether it might provide a biomarker of glioma risk, survival, and immune dysfunction. Cluster models were used to examine the relationship between CCL22 and glioma risk. Patient survival was assessed using Cox regression models. We also examined the relationship between CCL22 levels and CD4 cell counts, as well as allergy history and IgE levels. CCL22 levels were significantly lower among glioma cases compared to controls (Mean±SEM: 1.23±0.03 ng/mL in cases versus 1.60±0.03 ng/mL in controls, P<0.0001), and this difference remained significant even after controlling for other covariates in the cluster models (highest quartile versus lowest Odds Ratio=0.21, P<0.0001). CD4 cell counts were positively correlated with CCL22 in glioma cases (Spearman r2=0.51, P<0.01) and were significantly lower in cases compared with controls. Higher CCL22 levels were associated with longer survival in all cases combined and in GBM cases (hazard ratioallcases=0.81; 95% CI: 0.72–0.91, P=0.0003). CCL22 levels were not associated with IgE level or self-reported allergies. Circulating CCL22 levels are related to both glioma risk and survival duration independent of age, histology, grade and IDH mutation status. CCL22 should be considered a marker of immune status with potential prognostic value.

Targeting TGF-β Signaling for Therapeutic Gain

“…Moreover, highmedian MDC was associated with longer OS (11 mo) than low-median MDC (4.7 mo). This correlation was seen across all experimental arms, and has previously been reported as a prognostic factor for glioblastoma in general (Zhou et al 2015). Circulating TGF-b levels did not significantly associate with OS, al- though nine patients with TGF-b1 levels greater than the median, who were treated with galunisertib monotherapy, had a median OS of 11 mo, compared with an OS of 4.7 mo for the other 30 patients in the same treatment arm whose pretreatment TGF-b1 levels were less than the median (Brandes et al 2016).…”

CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment

“…Interestingly, all high-scoring epitopes were located in the signal peptide portion of the sequence, which is cleaved off before the protein is secreted. One of the high-scoring CCL22-derived peptides was RLQTALLVVL, hereafter referred to as pCCL22 [3][4][5][6][7][8][9][10][11][12] . To characterize pCCL22 [3][4][5][6][7][8][9][10][11][12] -specific T cells, we acquired peripheral blood mononuclear cells (PBMCs) from a melanoma patient and stimulated these cells using autologous dendritic cells (DCs) or PBMCs pulsed with the pCCL22 [3][4][5][6][7][8][9][10][11][12] peptide.…”

“…1E), indicating that T2 cells could cross-present the pCCL22 [3][4][5][6][7][8][9][10][11][12] epitope even without TAP expression in these cells. We then examined the T-cell avidity of pCCL22 [3][4][5][6][7][8][9][10][11][12] -specific T cells toward the pCCL22 [3][4][5][6][7][8][9][10][11] peptide (RLQTALLVV), which is one amino acid shorter than pCCL22 [3][4][5][6][7][8][9][10][11][12] and was predicted by the computer algorithm to bind to HLA-A2 with high affinity. Although the T cells reacted toward both peptides, they showed the highest avidity toward the decamer pCCL22 3-12 epitope (Fig.…”

“…Its ligand CCL22 is abundantly expressed in many types of human cancer, including ovarian and prostate tumors, gliomas, and esophageal, gastric, and breast carcinomas. [4][5][6][7][8] CCL22 reportedly promotes Treg recruitment to cancer tissue. 4,5 Zou and colleagues first described the importance of CCL22 for the specific recruitment of Tregs, which foster immune privilege.…”

Atopic Diseases Correlated with the Incidence of Cancer

“…This inverse association may result from reverse causality. Because the tumor itself can suppress the immune system [6], patients with malignant tumors often exhibit immunological defects (e.g., a delayed hypersensitivity response or a reduced number of circulating T cells) [7]. Eczema is considered to be a chronic state of inflammation in certain tissues, which makes it responsible for the positive associations observed with cancer risk.…”