ARTICLE ABSTRACT
Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed.
We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and loss of heterozygosity from chromosomal uniparental disomy. Lastly, immune profiles of patients with recurrence were compared with those of patients without recurrence.
HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, PD-L1 expression, and the immune infiltration score. HCC tumors that exhibited a global loss of heterozygosity from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global loss of heterozygosity and aerobic glycolysis.
These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers.
