Neoadjuvant immunotherapy pre-cancer surgery relieves tumor-specific CD8+T-cell dysfunction and restores memory differentiation potential

Abstract Recent preclinical and clinical results indicate that neoadjuvant immunotherapy pre-surgery may be superior to surgery followed by adjuvant immunotherapy, however it is unclear why. Using preclinical mouse models of spontaneously metastatic cancer, we dissected the mechanisms underpinning the improved efficacy of neoadjuvant immunotherapy. Compared to adjuvant treatment, neoadjuvant treatment promoted the expansion, subsequent contraction, and memory differentiation of tumor-specific CD8+ T-cells. This process “resets” the antitumor immune response to one more reminiscent of that which occurs during an acute viral infection. These effects required the presence of the primary tumor followed by its timely resection but was independent of de novo priming of tumor-specific CD8+ T-cells. This understanding allowed us to identify an on-treatment biomarker within the blood that predicted long-term survival among neoadjuvant-treated mice. These findings may enable selective targeting of key pathways activated and further improvement of front-line cancer immunotherapies. Citation Format: Jake S. O'Donnell, Jing Liu, Stacey Allen, Scott Mueller, Mark J. Smyth, Michele W.L. Teng. Neoadjuvant immunotherapy pre-cancer surgery relieves tumor-specific CD8+ T-cell dysfunction and restores memory differentiation potential [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR02.