Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance.

CD73 is involved in tumor immune escape and promotes the growth and progression of cancer cells. The functional role of CD73 expression in papillary thyroid carcinoma (PTC) has not yet been established. In 511 patients with PTC, immunohistochemistry for CD73 on tissue microarrays showed that the high expression of CD73 was associated with an aggressive histologic variant (p = 0.002), extrathyroidal extension (p < 0.001), lymph node metastasis (p < 0.001), and BRAFV600E mutation (p = 0.015). Survival analysis results showed that patients with high CD73 expression had worse recurrence-free survival (p = 0.023). CD73 inhibitors induced G1 cell cycle arrest and apoptosis, inhibited the migration and invasion of PTC cells, and suppressed tumor growth in PTC xenograft nude mice. High expression of CD73 (NT5E) mRNA was associated with unfavorable clinicopathologic characteristics, the abundance of Tregs and dendritic cells, depletion of natural killer (NK) cells, and high expression of immune checkpoint genes and epithelial-to-mesenchymal transition-related genes in The Cancer Genome Atlas (TCGA) dataset. Taken together, CD73 expression promotes tumor progression and predicts low recurrence-free survival. Targeting the CD73–adenosine axis in the tumor microenvironment offers an attractive pathway for therapeutic strategies aimed at advanced PTC.

Patients with papillary thyroid carcinoma (PTC) have excellent survival, but recurrence remains a major problem in the management of PTC. We aimed to determine the prognostic impact of the expression of CD10 and CD15 in patients with PTC. Immunohistochemistry for CD10 and CD15 was performed on the tissue microarrays of 515 patients with PTC. The expression of CD10 and CD15 was detected in 201 (39.0%) and 295 (57.3%) of 515 PTC cases, respectively, but not in the adjacent benign thyroid tissue. Recurrence was inversely correlated with CD15 expression (p = 0.034) but not with CD10 expression. In 467 PTC patients treated with radioiodine remnant ablation, the CD15 expression had an adjusted hazard ratio of 0.500 (p = 0.024) for recurrence-free survival and an adjusted odds ratio of 2.678 (p = 0.015) for predicting long-term excellent therapeutic response. CD10 expression was not associated with clinical outcomes. In the Cancer Genome Atlas dataset, the expression level of FUT4 (CD15) mRNA was higher in the low/intermediate-risk group for recurrence than in the high-risk group and exhibited positive correlation with SLC5A5 (NIS) mRNA expression (p = 0.003). Taken together, CD15 expression was identified as an independent prognostic marker for improved prognosis in PTC patients.

B cell activating factor (BAFF) is a cytokine that plays a role in the survival, proliferation and differentiation of B cells. We proposed to observe the effects of BAFF inhibition on the humoral immune responses of an allosensitized mouse model using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and were treated with anti-BAFF monoclonal antibody (mAb) (named Sandy-2) or control IgG1 antibody. HLA.A2-specific IgG was reduced in BAFF-inhibited mice compared to the control group (Δ-13.62 vs. Δ27.07, p < 0.05). BAFF inhibition also resulted in increased pre-pro and immature B cell proportions and decreased mature B cells in the bone marrow (p < 0.05 vs. control). In the spleen, an increase in transitional B cells was observed with a significant decrease in marginal and follicular B cells (p < 0.05 vs. control). There was no significant difference in the proportions of long-lived plasma and memory B cells. Microarray analysis showed that 19 gene probes were significantly up- (>2-fold, p < 0.05) or down-regulated (≤2-fold, p < 0.05) in the BAFF-inhibited group. BAFF inhibition successfully reduced alloimmune responses through the reduction in alloantibody production and suppression of B cell differentiation and maturation. Our data suggest that BAFF suppression may serve as a useful target in desensitization therapy.

Background The combination immunotherapy (CIT), administering both nivolumab and ipilimumab, has demonstrated the durable efficacy in patients with skin cutaneous melanoma (SKCM), kidney renal cell carcinoma (KIRC), and lung adenocarcinoma (LUAD). However, the survival benefits of the CIT vary among responders according to tumor type and thus, the biomarker development for CIT is necessary for predictive, preventive, and personalized (3P) medicine. Purpose To understand the mechanisms underlying the differential clinical efficacy and to explore the predictive biomarkers of the CIT, we analyzed transcriptome-based immune landscapes in SKCM, KIRC, and LUAD. Methods We obtained bulk tumor RNA-Seq data of LUAD (n=517), KIRC (n=506), and SKCM (n=472) from the Cancer Genome Atlas (TCGA) consortium and examined gene signature-based tumor-infiltrating immune cell profiles, as well as the correlations among expression levels of immune checkpoints and individual tumor mutational burden (TMB). Results Immunoprofiling revealed three subgroups of hot, intermediate, and cold clusters according to immune cell infiltration patterns for three tumor types examined. Among the relationship between immune checkpoints, CTLA-4 and PD-1 levels from LUAD and KIRC tumors were predominantly upregulated in immune-hot subgroups and exhibited strong concordance with each other (Spearman’s r=0.75 for LUAD; r=0.75 for KIRC). SKCM tumors were distinguished from LUAD and KIRC by manifesting relatively weaker correlations between PD-1 and CTLA-4 expression (r=0.58). Further analyses in the LUAD cohort presented that expression levels of immune checkpoints were dependent upon individual patient TMB, while overall tumor-infiltrating patterns of immune cells were poorly correlated with the mutational burden except the CD56dim NK cell subset. Conclusion Our data suggest that the gene signature-based profiling of tumor-infiltrating immune cells guides us to a better understanding of an immune landscape of the tumor immune microenvironment (TIME), and to predict the clinically demonstrated efficacy of the CIT in each cancer type. Therefore, CIT implemented through a more comprehensive characterization of immune features in individual patient’s tumors may enhance the clinical benefit of the predictive, preventive, personalized medicine (3PM) in cancer patients.