The neoantigen landscape and immune regulators in cervical cancer.

Abstract

5528 Background: Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. Methods: To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides using exome and RNA sequencing data of a large number of tumors in two independent data sets (n = 194 and 79), and analyzed whether mutation and neoantigen load correlate with expression of genes involved in antigen presentation, infiltrating immune cell type markers, and HPV oncoprotein-associated genes. Normal tissue expression analyses were also performed using data from the Genotype-Tissue Expression project (n = 8,555). Results: We found that potentially immunogenic and targetable neoantigens can be predicted for almost all cervix tumors, including recurrent neoantigens from mutations of known oncogenic driver genes (KRAS G12D, MAPK1 E322K, PIK3CA E545K, PIK3CA E542K, ERBB2 S310F, and ERBB3 V104M). Furthermore, we found that expression of HPV-associated “master regulator” genes is associated with mutation, neoantigen, and HPV load, and also with expression of several important markers in the immune microenvironment. Notably, the OVOL1 master regulator positively correlated with mutation and neoantigen load, and also with PD-L1 and TGFB1 expressions. Furthermore, ENO1 over-expression in cervical cancer was associated with high HPV load, and ENO1 level also positively correlated with PD-L1 and TGFB1 expressions, suggesting that it may be a potential target in cervical cancer. Conclusions: For most of the cervix tumors we report predicted neoantigens, and we also identified recurrent neopeptides derived from mutations in known oncogenes. We have also identified statistically significant associations between neoantigen availability, antigen presentation, cytotoxic T-cell function, suppressive mechanisms, and expression of HPV master regulators to help guide immunotherapies of cervical cancer.