Toby Ward, PhD
Field Applications Scientist

The importance of cellular neoantigens for immuno-oncology in virus-associated cancers

Approximately 12% of human cancers are associated with viral infection, including a majority of cervical cancers, Merkel cell carcinomas, and oropharyngeal cancer cases, along with significant proportions of other head and neck cancers and hepatocellular carcinomas. Viral infection can directly lead to cellular transformation via expression of viral oncoproteins (e.g. in the case of human papillomaviruses), or can contribute to oncogenesis indirectly by creating an inflammatory tissue environment (e.g. hepatitis B and C viruses). Human malignancies that harbor tumorigenic viruses, such as Epstein-Barr virus (EBV, nasopharyngeal carcinoma and some Burkitt’s lymphomas), Merkel Cell Polyoma virus (Merkel cell carcinoma), Hepatitis B virus (HBV, hepatocellular carcinoma) or Human Papillomavirus (HPV, cervical, oropharyngeal and other cancers), express viral antigens that can be used to trigger immune responses through the use of tumor vaccines or other immune-priming strategies.

These non-self, virus-encoded antigens can serve as targets for cytotoxic T-cells, and are already being employed in the clinical treatment of virus-associated malignancies such as cervical cancer and nasopharyngeal carcinoma. In a 2014 study, vaccination (DNA priming followed by vaccinia vector boost) with the E6 and E7 oncoproteins of HPV, led to immune-induced regression of high grade cervical dysplasia (Maldonado, et al., Science Translational Medicine 29 Jan 2014: Vol. 6, Issue 221, pp. 221ra13).

In addition to virus-encoded antigens, transformed cancer cells may also accumulate mutations that give rise to neoepitopes within cellular proteins. Thus, in addition to canonical non-self viral proteins, a suite of neoantigens within the cellular proteome may also be present and displayed by tumor cells, and has the potential for enhancing strategies to trigger anti-tumor immunity (such as cancer vaccines).

At the 2017 Keystone Symposium, Dr. Sanja Stevanovic, in a talk entitled “Landscape of Immunogenic Tumor Antigens in Successful Immunotherapy of Virally-Induced Epithelial Cancer”, presented data from two patients with HPV+ tumors, who experienced complete regression of HPV+ metastatic cervical cancer after receiving tumor-infiltrating adoptive T-cell therapy. Using immunogenomics, including exome and transcriptome sequencing of the primary tumor lesions, as well as T-cell receptor (TCR) sequencing, the investigators found that the majority of responding anti-tumor T-cells were reactive to cellular, and not viral, antigens. In addition, virus-specific T cells did not display preferential in vivo expansion during cancer regression, showing that T-cells specific to cellular neoantigens were capable of response and expansion in these patients. Together, these data reveal a significant role for infiltrating immune cells that target altered cellular proteins/neoantigens, in addition to the cytotoxic immune response mounted against the foreign viral antigens.

These data demonstrate that it is important to ascertain the entire neoantigen landscape within tumors harboring oncogenic viruses. While the expressed viral (foreign) proteins (e.g. HPV E6, E7 proteins) are obvious targets for immunotherapy approaches and may be applicable across patients with virus associated tumors, many of the responding T-cells may be specific to neoepitopes residing in mutated cellular (self) proteins. Improved vaccination strategies may incorporate not only canonical viral target proteins, but also tumor-specific cellular neoantigens, in order to increase the diversity and efficacy of T-cell responses. To this end, immunogenomics sequencing assays which interrogate the full exome and transcriptome of tumors are well powered to identify expressed, private cellular neoantigens that may be suitable for immunization.