Abstract
The importance of anti-tumor immunity by CD8+ T cells is well defined, but antigen-specific immune monitoring for CD8+ responses across many potential tumor antigens is expensive and difficult. This difficulty is compounded by increasing evidence that every tumor has unique mutant neoepitopes. We hypothesized that new technologies in peptide printing might allow us to partially overcome this obstacle by instead characterizing antibody responses against a paired array of neoepitope and native peptides.
We designed a 15-mer peptide array of mutated and native peptides from the murine mammary carcinoma 4T1 and used it to characterize the serum IgG antibody responses to vaccination with 4T1 autophagosome-enriched vaccine (DRibbles), poly-IC adjuvant, the combination of both, or naïve animals across 4 independent experiments. This array was printed by JPT peptides and included 75 pairs of single-nucleotide polymorphic and native peptides identified by both our own whole exome sequencing and the current 4T1 literature. We also included other sequences of interest to 4T1 immunity such as the retrovirus fragment AH1. MHCI peptide predictions were robust and used the top NetMHCpan v2.8 score from all possible windowed 8,9,10, and 11-mers for H2-Kd,Ld, and Dd surrounding the mutation site in its native protein context.
The results of this work identify a linear correlation between higher predicted peptide MHCI binding affinity and the IgG antibody signals increased in combination treated groups versus controls. Linear regression analysis demonstrates that normalized antibody responses to mutated and native 4T1 peptides are more likely to be higher in sera from autophagosome-enriched vaccine plus poly-IC treated animals than naïve animals if these peptides contain higher affinity domains for MHCI (p<.0001). This correlation is not significant in the groups treated with vaccine or adjuvant alone. Animals pre-treated with this combination therapy also benefit from a significant delay in tumor growth upon challenge with 4T1 versus naïve animals (p<.001).
These results identify a previously unknown link between predicted MHCI binding affinity and the anti-tumor antibody response following combination immunotherapy - suggesting some antigen-specific interaction between B cells and CD8+ T cells that might be exploited to improve the immune monitoring of cancer therapies.
Citation Format: Tyler W. Hulett, Shawn Jensen, Christopher Dubay, Carlo Bifulco, Michael Afentoulis, Ashok Reddy, Larry David, Bernard A. Fox. Increased IgG antibody responses to neoepitope and native peptides containing high affinity domains for MHCI following combination cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4900.
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