Farhad Ghasemi

Cancers progress when the immune system fails to identify and eliminate malignant cells. Recognition of this, combined with advances in tumor immunology, has allowed development of therapies that induce effective anti-tumor immune responses. For incompletely-understood reasons, effective responses to immunotherapy occur in some patients and not others. Head and neck squamous cell carcinomas (HNSCC) are a common cancer type that can be divided into two subsets based on human papillomavirus (HPV) status. HPV status is a strong predictor of positive clinical outcome. Expression of exogenous viral antigens by HPV+, but not HPV-, HNSCC allows direct comparison of the immune status (immune cell presence and characteristics) between these two otherwise anatomically-similar tumors. Using TCGA data, we compared the immune landscape between HPV+ and HPV- treatment-naïve HNSCC. As compared to HPV- samples, HPV+ HNSCC exhibited a strong Th1 response characterized by increased infiltration with multiple types of immune cells and expression of their effector molecules. HPV+ HNSCC also expressed higher levels of CD39 and multiple T-cell exhaustion markers including LAG3, PD1, TIGIT, and TIM3 compared to HPV- HNSCC. Importantly, patients with higher expression of these exhaustion markers-indicative of a T-cell-inflamed tumor-correlated with markedly improved survival in HPV+, but not HPV-, HNSCC. Thus, profound differences exist between the immune landscape of HPV+ and HPV- HNSCC. These results suggest that immune checkpoint inhibitor therapy is a promising treatment strategy for HPV+ HNSCC, and that expression of immune checkpoint molecules could serve as a predictive biomarker of patient outcome in HPV+ HNSCC.

Human papillomavirus (HPV) causes an increasing number of head and neck squamous cell carcinomas (HNSCCs). Altered metabolism contributes to patient prognosis, but the impact of HPV status on HNSCC metabolism remains relatively uncharacterized. We hypothesize that metabolism-related gene expression differences unique to HPV-positive HNSCC influences patient survival. The Cancer Genome Atlas RNA-seq data from primary HNSCC patient samples were categorized as 73 HPV-positive, 442 HPV-negative, and 43 normal-adjacent control tissues. We analyzed 229 metabolic genes and identified numerous differentially expressed genes between HPV-positive and negative HNSCC patients. HPV-positive carcinomas exhibited lower expression levels of genes involved in glycolysis and higher levels of genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, and β-oxidation than the HPV-negative carcinomas. Importantly, reduced expression of the metabolism-related genes SDHC, COX7A1, COX16, COX17, ELOVL6, GOT2, and SLC16A2 were correlated with improved patient survival only in the HPV-positive group. This work suggests that specific transcriptional alterations in metabolic genes may serve as predictive biomarkers of patient outcome and identifies potential targets for novel therapeutic intervention in HPV-positive head and neck cancers.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Antigen-presenting cells (APCs) present peptide antigens in the context of the class-II major histocompatibility complex (MHC-II). During inflammatory conditions, epithelial cells express MHC-II and function as accessory APCs. Utilizing RNA-seq data from nearly 400 GC patients, we determined the impact of EBV-status on expression of MHC-II components, genes involved in their regulation, and T-cell co-stimulation. Virtually all MHC-II genes were significantly upregulated in EBVaGCs compared to normal tissues, or other GC subtypes. Genes involved in antigen presentation were also significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5. This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. Furthermore, MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. In addition, expression of co-stimulatory molecules involved in T-cell activation and survival was also significantly increased in EBVaGCs. Thus, gastric adenocarcinoma cells may functionally contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs via a previously unappreciated role in interferon-induced antigen presentation.