Newly Emerged Immunogenic Neoantigens Enable To Break The Resistance Of Immune Checkpoint Inhibitors.

Abstract Immune checkpoint inhibitors (ICIs) and other cancer immunotherapies resurge T cell responses that target tumor antigens expressed by cancer cells, particularly tumor neoantigens derived from genetic alterations. However, tumors establish immune escape mechanisms during tumor development and progression, including the loss of pre-existing tumor antigens and impaired T cell responses. In the last decade, various strategies to overcome the immune escape mechanisms have been investigated in the clinic to achieve a cure for cancer. Here, we show that a newly emerged immunogenic neoantigen changes the tumor environment and inhibits tumor growth. To develop animal models, we employed a Tet-on gene expression system, in which immunogenic neoantigens including chicken ovalbumin (OVA) and human cancer-testis antigen NY-ESO-1 were newly emerged upon doxycycline (Dox) treatment. MC-38 (colorectal cancer) inducing OVA, CT26 (colorectal cancer) inducing NY-ESO-1 and B16 (melanoma) inducing NY-ESO-1 were developed, and these cell lines were administered into mice. Induction of these model neoantigens by Dox treatment after tumor establishment (approximately 8~10 mm) significantly inhibited tumor growth. The antitumor effects were not observed in nude mice lacking T cells or CD8+ T-cell depleted mice, indicating an important role of CD8+ T cells. Furthermore, PD-1/PD-L1 blockade further enhanced CD8+ T cell responses against the newly emerged immunogenic neoantigens, resulting in a far stronger tumor growth inhibition. We then propose that newly-emerged immunogenic neoantigens are sufficient to induce antitumor effects that can overcome immune escape mechanisms in the tumor microenvironment, thereby inhibiting tumor growth and that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to ICI therapy. Citation Format: Daisuke Sugiyama, Tomoaki Muramatsu, Takuro Noguchi, Yoshiki Akatsuka, Hiroyoshi Nishikawa. Newly emerged immunogenic neoantigens enable to break the resistance of immune checkpoint inhibitors [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 1803.