BRAF^V600E in Papillary Thyroid Carcinoma Is Associated with Increased Programmed Death Ligand 1 Expression and Suppressive Immune Cell Infiltration

Abstract

Background: There remain a small number of patients with papillary thyroid cancer (PTC) who suffer recurrence, metastases, or death. While mutation of the BRAF gene, corresponding to the constitutively active BRAF V600E protein, has been associated with worse clinical outcomes in thyroid cancer, the reasons underlying this observation are presently unknown. Disruption of endogenous host immune surveillance and promotion of tumor immune escape is one mechanism by which BRAF V600E tumors may achieve more aggressive behavior. This study evaluated the relationship between BRAF V600E status and known strategies of tumor-mediated immune suppression. Methods: Tissue sections of PTC tumors from 33 patients were evaluated by immunohistochemistry for tumorexpressed suppressive ligands and enzymes and effector and suppressor populations of tumor-infiltrating immune cells. Presence of BRAF V600E was evaluated by direct DNA sequencing of PTC specimens and the results correlated with tumor-expressed molecules and tumor-infiltrating immune cell populations, as well as patient characteristics and pathologic findings. Results: BRAF V600E tumors more often express high levels of immunosuppressive ligands programmed death ligand 1 (53% vs. 12.5%) and human leukocyte antigen G (41% vs. 12.5%) compared to BRAF wild-type tumors. There was no association between indoleamine 2,3-dioxygenase 1 expression and BRAF V600E status. Furthermore, BRAF V600E tumors demonstrate both lower CD8 + effector to FoxP3 + regulatory T cell, and CD68 + pan-macrophage to CD163 + M2 macrophage ratios, indicating relative increases in suppressive T cell and macrophage components, respectively. Conclusions: Overall, BRAF V600E PTC tumors display a broadly immunosuppressive profile and evidence of disturbed host tumor immune surveillance that may contribute to the poorer outcomes observed in this subset of patients with thyroid cancer.

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

“…These results demonstrate that a strongly immunosuppressive molecular profile may be elicited in the tumor microenvironment of papillary thyroid carcinomas positive for the BRAF V600E mutation, suggesting that the promotion of tumor immune escape may be a mechanism by which the BRAF V600E mutation may contribute to aggressive tumor behavior (Angell et al 2014). Following this rationale, Brauner and coworkers thoroughly investigated the PD-1/PD-L1 immune checkpoint mechanism in a thyroid cancer model (Brauner et al 2016).…”

“…Angell and coworkers demonstrated that papillary thyroid carcinomas harboring the BRAF V600E mutation frequently express PD-L1 (Angell et al 2014). Similarly, positivity for the BRAF V600E mutation was associated with the expression of HLA-G (a nonclassical and inhibitory MHC class I molecule).…”

The immune network in thyroid cancer

“…The latter findings suggest a Braf-driven tumor-promoting microenvironment. 103 CD4 C cells CD4 C T helper (Th) lymphocytes are a heterogeneous population. Th1-mediated immunity is generally considered as antitumoral, while polarized Th2 and/or Treg activity is believed protumorigenic.…”

Perspectives for immunotherapy in endocrine cancer

“…In contrast, BRAF V600E positivity had no impact on TAM (CD68+ or CD163+ positive macrophages) content in PTCs (Angell et al 2014). This observation leads to the hitherto unresolved question whether mutational features and/or load (e.g.…”

“…Several studies have shown a correlation of tumor PD-L1 expression and response to anti-PD-1/ PD-L1 treatment (Herbst et al 2014, Borghaei et al 2015, Garon et al 2015, whilst others did not (Larkin et al 2015, McDaniela 2015, Robert et al 2015b. Furthermore, one methodological problem using PD-L1 as a single biomarker might be that different antibodies are Angell et al 2014, Robert et al 2015a. In addition, harmonization of IHC protocols and definition of reliable cut-offs for quantification of PD-L1 staining is still missing with most tests focusing on PD-L1 expression on tumor cells (Borghaei et al 2015) while others also include myeloid cells (Herbst et al 2014).…”