Abstract PR02: Antigen delivery targeting tumor-infiltrating macrophages leads to eradication of tumor highly resistant to immune checkpoint inhibitors

Recently, immune checkpoint inhibitors using anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies has been emerging as novel, effective modality for the treatment of cancer. However, immune checkpoint inhibitors have been proven to be effective only for a partial group of patients who have lymphocyte infiltration or inflammation in the tumor microenvironment prior to the treatment. Although the relationship between efficacy of checkpoint inhibitors and anti-tumor cellular immune response has been revealed, these studies paid attention only for the induction of immune responses in lymph node and do not pay attention to the mechanisms regulating the anti-tumor cellular immune responses in tumor site. In this study, by using checkpoint inhibitors-sensitive or resistant murine in vivo tumors, we explored a mechanism underlying the resistance focusing on immune cells at the tumor site. We newly identified CD11b+/F4/80+ tumor-associated macrophages as a key factor highly correlated to the resistance. In the resistant tumor, tumor-associated macrophages remained immature and did not exert antigen-presenting activity. A nanogel-based antigen delivery system enabled to selectively and efficiently deliver a long peptide antigen to tumor-associated macrophages. Co-administration of the nanogel:long peptide antigen and TLR agonist activated tumor-associated macrophages and induced antigen presentation by these cells. This change in the tumor microenvironment turned the resistant tumor to treatment-sensitive, in particular, adoptive transfer of TCR-engineered T cells after the treatment with nanogel:long peptide antigen and TLR agonist resulted in the cure of resistant tumor. These results indicate that the status and function of tumor-associated macrophages have a great impact on treatment sensitivity, and that these cells might be a promising target to improve the efficacy of immunotherapy including checkpoint inhibitors and adoptive cell therapies. This abstract is also being presented as Poster B68. Citation Format: Daisuke Muraoka, Naozumi Harada, Naohiro Seo, Tae Hayashi, Keisuke Fujii, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Hideo Yagita, Kazunari Akiyoshi, Hiroshi Shiku. Antigen delivery targeting tumor-infiltrating macrophages leads to eradication of tumor highly resistant to immune checkpoint inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr PR02.