Abstract 1571: Neoantigen vaccine plus CD38 blockade suppress the proliferation of murine cold lung cancer LLC1

Abstract Immune checkpoint inhibitors are now the mainstay for the treatment of lung cancer. However, so-called cold tumors are known to be resistant to checkpoint inhibitors. Neoantigens associated with genetic mutations of the tumor have the potential to stimulate a potent and highly specific immune response. To develop effective immunotherapy for cold lung cancer, we examined whether neoantigen-based immunotherapy can develop immune responses and display anti-tumor effects on the cold lung cancer model, Lewis lung carcinoma cells (LLC1) resistant to anti-CTLA-4 or anti-PD-1 therapy. LLC1 cells were subjected to whole-exome and RNA sequencing. Mutation-associated neoantigens were predicted and prioritized by their affinity to MHC class I molecules and their expression. Using netMHCpan, sixty mutated peptides with IC50 <200 nM and 68 mutated peptides with IC50>200 nM, but the wild to corresponding mutated peptide ratio of binding affinity>10 were selected as candidate neoantigens. C57BL/6 mice were immunized with dendritic cells pulsed with these neoantigen short peptides (8-10mer). Twenty-five out of 128 short mutated peptides induced peptide-specific CD8+ T cell response to some extent. Next, 25 long peptides (21mer), which incorporated corresponding immunogenic short peptide sequences, were synthesized and used to immunize mice. DC vaccines pulsed with neoantigen in long peptide format (LP) induced both CD4+ and CD8+ T cell response ex vivo. Of them, DC pulsed with LP82 partly delayed the LLC1 growth in vivo. By RNA-Seq, CD38 was highly expressed in LLC1. Thereby, an anti-CD38 antibody was administered in LLC1-bearing mice immunized with DC pulsed with LP82. The tumor growth was suppressed in the combination treatment. Although CD38 plays an important role in converting nicotinamide adenine dinucleotide (NAD+) to adenosine, adenosine receptor antagonist could not inhibit the tumor growth in mice immunized with LP82. Alternatively, NAD+ accumulation due to CD38 blockade decreased regulatory T cells in the tumor immune microenvironment, consistent with the decreased Foxp3+ transcription and increased IFNg and IL2 production of CD4+ T cells sorted from tumor immune microenvironment. Our study suggested that the prioritization of neoantigens that can induce anti-tumor response is critical for developing neoantigen-targeting immunotherapy. Combining an effective neoantigen vaccine and precise immune modulator could enhance anti-tumor activities even in cold lung tumors. Citation Format: Changbo Sun, Koji Nagaoka, Akihiro Hosoi, Yukari Kobayashi, Jun Nakajima, Kazuhiro Kakimi. Neoantigen vaccine plus CD38 blockade suppress the proliferation of murine cold lung cancer LLC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1571.