Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth

Abstract

The threshold for immunogenic clonal fraction in a heterogeneous solid tumor required to induce effective bystander killing of non-immunogenic subclones is unknown. Pancreatic cancer poses crucial challenges for immune therapeutic interventions due to low mutational burden and consequent lack of neoantigens. Here, we designed a model to incorporate artificial neoantigens into genes of interest in cancer cells and to test the potential of said antigens to actuate bystander killing. By precisely controlling the abundance of a neoantigen in the tumor, we studied the impact of neoantigen frequency on immune response and immune escape. Our results showed that a single, strong, widely expressed neoantigen could lead to a robust antitumor response when at least 80% of cancer cells express the neoantigen. Further, immunological assays revealed induction of T-cell responses against a non-target self-antigen on KRAS oncoprotein, when we inoculated animals with a high frequency of tumor cells expressing a test neoantigen. Using nanoparticle-based gene therapy, we successfully altered the tumor microenvironment by perturbing interleukin-12 and interleukin-10 gene expression. The subsequent remodeling of the microenvironment reduced the threshold of neoantigen frequency at which bioluminescent signal intensity for tumor burden decreased 1.5-logfold, marking a robust tumor growth inhibition, from 83% to as low as 29%. Our results thus suggest that bystander killing is rather inefficient in immunologically cold tumors like pancreatic cancer and requires an extremely high abundance of neoantigens. However, the bystander killing mediated antitumor response can be rescued, when supported by adjuvant immune therapy.

Neoantigens and their clinical applications in human gastrointestinal cancers

“…However, PC is crucially challenging for immune therapeutic interventions because of the low TMB and absence of neoantigens [180]. As clarified by Das et al, bystander killing process is not sufficient in immunologically "cold" tumors, such as PC, and there is a need for high neoantigen abundance for inducing effective bystander killing of non-immunogenic subclones [181]. However, the focus of efforts for developing more efficient and safer therapies for PC is on the development of neoantigen-based immunotherapy, such as anticancer vaccines, immune checkpoint inhibitors, antibodytargeted therapies, and adoptive T cell transfer [180,182,183].…”

Towards an updated view on the clinical management of pancreatic adenocarcinoma: Current and future perspectives (Review)

“…The larger the variability of these neoantigens the greater the immunogenicity and the higher the immune response. In the specific case of pancreatic cancer, one of the main problems encountered in recent years is the low variability of tumor antigens compared with that in other tumors (129). While some tumors such as colon and lung tumors present with 100-1,500 neoantigens, pancreatic cancer presents with 10-60 (130,131).…”