Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients

Abstract

The chemokine CCL22 recruits regulatory T (T-reg) cells into tumor tissues and is expressed in many human tumors. However, the prognostic role of CCL22 in cervical cancer (CC) has not been determined. This study retrospectively analyzed the clinical significance of the expression of CCL22 and FOXP3 in 230 cervical cancer patients. Immunohistochemical staining analyses of CCL22 and FOXP3 were performed with a tissue microarray. Double immunofluorescence staining, cell coculture, and ELISA were used to determine CCL22 expressing cells and mechanisms. The higher number of infiltrating CCL22+ cells (CCL22 high ) group was associated with lymph node metastasis (p = 0.004), Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stages (p = 0.010), therapeutic strategies (p = 0.007), and survival status (p = 0.002). The number of infiltrating CCL22+ cells was positively correlated with that of infiltrating FOXP3+ cells (r = 0.210, p = 0.001). The CCL22 high group had a lower overall survival rate (OS), compared to the CCL22 low group (p = 0.001). However, no significant differences in progression free survival (PFS) were noted between the two groups. CCL22 high was an independent predictor of shorter OS (HR, 4.985; p = 0.0001). The OS of the combination group CCL22 high FOXP3 high was significantly lower than that of the combination group CCL22 low FOXP3 low regardless of the FIGO stage and disease subtype. CCL22 high FOXP3 high was an independent indictor of shorter OS (HR, 5.284; p = 0.009). The PFS of group CCL22 high FOXP3 high was significantly lower than that of group CCL22 low FOXP3 low in cervical adenocarcinoma, but CCL22 high FOXP3 high was not an independent indicator (HR, 3.018; p = 0.068). CCL22 was primarily expressed in M2-like macrophages in CC and induced by cervical cancer cells. The findings of our study indicate that cervical cancer patients with elevated CCL22+ infiltrating cells require more aggressive treatment. Moreover, the results provide a basis for subsequent, comprehensive studies to advance the design of immunotherapy for cervical cancer.

Development and Validation of an Immune-related Prognostic Signature in Cervical Cancer

“…CD74 has the potential to be a therapeutic target in cancer and autoimmune disease [36]. The chemokine CCL22 promoted regulatory T cell communication with dendritic cells to control immunity and was associated with poor prognosis [37,38]. CH25H produces 25-hydroxycholesterol, which inhibited tumor-derived extracellular vesicles uptake and correlated with prognosis in melanoma patients [39].…”

Development and validation of an immune-related prognostic signature in cervical cancer

“…CD74 has the potential to be a therapeutic target in cancer and autoimmune disease [39]. The chemokine CCL22 promoted regulatory T cell communication with dendritic cells to control immunity and was associated with poor prognosis [40,41]. CH25H produces 25-hydroxycholesterol, which inhibited tumor-derived extracellular vesicles uptake and correlated with prognosis in melanoma patients [42].…”

Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

“…CCL22, the dominant CCR4 ligand for Treg recruitment in tumors, has been described in different solid tumors (breast and cervical cancers, glioblastoma, squamous cell carcinoma (SCC), CRC and PDAC), where its expression correlates with Treg infiltrate and poor prognosis [ 22 , 25 , 31 , 46 , 66 , 67 , 68 , 69 , 70 ]. However, in several tumors, including gastric carcinoma, CCL17 has also been reported to participate in CCR4 + Treg chemoattraction [ 71 ].…”

“…CCL22 is produced by tumor-associated macrophages (TAM) and DC in CRC and PDAC [ 70 ], cervical carcinoma [ 25 ], HNSCC [ 66 , 72 ] and ovarian carcinoma [ 22 ]. The production of CCL22 is induced by inflammatory soluble mediators present in the TME, such as tumor cell-derived IL-1α in CRC and PDAC [ 70 ].…”

“…Tregs are found at high frequencies in the tumor tissue of various types of solid tumors, such as breast [ 20 , 21 ] and ovarian [ 22 ] carcinoma, renal cell carcinoma (RCC) [ 23 , 24 ], cervix [ 25 ] and prostate [ 26 ] carcinoma, muscle invasive bladder carcinoma (MIBC) [ 27 ], non-small cell lung carcinoma (NSCLC) [ 28 ], hepatocellular carcinoma (HCC) [ 29 ], pancreatic adenocarcinoma (PDAC) [ 30 ], brain tumors [ 31 ], head and neck squamous cell carcinoma (HNSCC) [ 32 ] and melanoma [ 33 , 34 ]. Their high frequency among CD4 + T cells within tumor-infiltrating lymphocytes (TILs) or a high ratio of FOXP3 + Tregs to CD8 + T cells is associated with a poor prognosis in the majority of solid tumors (for review, [ 15 , 35 ].…”