Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation

Abstract

B7H1 is consistently associated with inhibition of the immune system in many solid tumors. However, there is no report about its impact on differentiated thyroid carcinoma (DTC) presentation, aggressiveness, or evolution. Aiming to investigate the role of B7H1 in DTC and correlate this protein with other tumor-infiltrating immune cells, we studied 407 thyroid nodule tissue samples including 293 from DTC patients, all managed according to a same standard protocol. In addition, we obtained 5 normal and 114 benign thyroid lesions. Eighteen out of the 253 papillary thyroid carcinomas were paired with respective metastatic lymph node tissues. B7H1 (CD274) protein expression was assessed by immunohistochemistry and the gene expression was quantified by real-time PCR. Malignant tissues displayed a more intense B7H1 staining and higher mRNA levels than benign tissues (both P!0.0001). We observed a positive linear correlation between higher age at diagnosis and B7H1 mRNA levels (PZ0.02896). Elevated levels of B7H1 protein were associated with the presence of CD4C, CD8C, CD20C, and FoxP3C lymphocytes (all P!0.05); tumor-associated macrophages (P!0.0001); and the presence of myeloid-derived suppressor cells (PZ0.03256). Stage II-IV patients presented higher B7H1 mRNA levels than stage I cases (PZ0.03522). On the contrary, a decreased expression of B7H1 protein was observed in lymph node metastasis (PZ0.0152). In conclusion, our data demonstrate that B7H1 expression is associated with features of aggressiveness, suggesting that this is an immune evasion mechanism of DTC cells.

The role of the inflammatory microenvironment in thyroid carcinogenesis

“…The expression of B7H1 in tumor cells has been reported to be associated with a poor prognosis in some epithelial cancers (Thompson et al 2006). We demonstrated that the expression of both B7H1 protein and B7H1 mRNA is upregulated in DTCs, contrasting with the low levels displayed by benign tissues (Cunha et al 2013). This result suggests that tumor cells may acquire B7H1 expression during the tumorigenic process.…”

“…Paired primary tumor and lymph node metastatic tissue samples were obtained from all the patients. We observed that the lymph node metastatic tissue samples had lower levels of B7H1 than the primary tumor tissue samples, indicating T-cell exhaustion (Cunha et al 2013). French et al (2012) have recently described high levels of IFNC/CD8C T cells in 12 metastatic lymph node tissue samples excised during the initial surgery at patient presentation.…”

“…This result suggests that tumor cells may acquire B7H1 expression during the tumorigenic process. We also observed an association between high B7H1 mRNA levels and the presence of some features of tumor aggressiveness, such as higher stages at presentation and increased age at diagnosis, suggesting that high levels of B7H1 expression may help identifying individuals who need a more aggressive approach (Cunha et al 2013). We also studied the expression of B7H1 in 18 patients with lymph node metastasis at diagnosis.…”

Dendritic cells in autoimmune disorders and cancer of the thyroid

“…However, immune system plays a substantial role also in later stages of tumour development. A modulation of the host defence into immune settings, supporting or not cancer cell survival, is assumed as one of the most important conditions governing the extend of tumour growth and spreading [66,67]. Numerous tumour specific and tissue damage associated humoral factors attract immune cells and modulate their functional properties [68][69][70][71].…”

“…Additionally, the local tumour specific microenvironment may lead to the induction of dominant tolerance mechanisms and in consequence to tumour immune escape. An expansion of various regulatory cell populations such as DCs [72,75,76], Tregs [67,74,77,78] or myeloid-derived suppressor cells [67,79,80] plays most probably a crucial role in this process. In thyroid carcinoma the process of infiltration with particular immune cell populations, including tumour associated monocytes, myeloid-derived suppressor cells, FoxP3 + Tregs, and other lymphocytic subsets, was correlated with tumour type and level of aggressiveness [67,[81][82][83].…”