Dissecting the Immunological Mechanisms underlying the Efficacy of Neoadjuvant Immunotherapy
Jing Liu1, Jake S. O'Donnell1,2,3, Stacey Allen1, Mark J. Smyth2,3, Michele W.L. Teng1,3 1Cancer Immunoregulation and Immunotherapy Laboratory, 2Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.3School of Medicine, University of Queensland, Herston, Queensland, Australia
Cancer immunotherapies targeting CTLA-4 and or PD-1/PD-L1 alone or in combination have elicited remarkable clinical responses in some advanced cancers. Recently, their efficacy in the treatment of earlier stages of disease has been demonstrated in an adjuvant setting. We previously demonstrated in two orthotopic mouse models of spontaneously metastatic breast cancer (4T1.2 and E0771), the significantly greater therapeutic power of neoadjuvant compared with adjuvant immunotherapies in the context of cancer surgery. Elevated and sustained peripheral tumor-specific CD8+ T cells after neoadjuvant immunotherapy underpinned the outcome. In this study, we demonstrated that Batf3+ DCs and type I IFN were critical for the efficacy of neoadjuvant anti-PD-1+anti-CD137 immunotherapy. Loss of Batf3+ DCs or blocking type I IFN receptor in neoadjuvant treated tumor-bearing mice significantly reduced tumor-specific activated CD8+ T cells in the blood and primary tumor. We next assessed how varying the scheduling and duration between neoadjuvant immunotherapies and surgery impacts on long-term survival. Importantly, maintaining the duration between resection of the primary 4T1.2 tumor and neoadjuvant anti-PD-1+anti-CD137 short (4 days) compared to long (10 days) was critical in generating long-term survivors. Interestingly, the addition of adjuvant combination immunotherapies (anti-PD-1+anti-CD137 or anti-CTLA-4+anti-PD-1) following their respective neoadjuvant treatment did not generally increase the proportion of long-term survivors. In contrast, biochemical immune-related adverse events (irAEs) increased in these tumor-bearing mice compared to similar groups that received only two doses of neoadjuvant combination immunotherapy. Overall, our data suggest that a short dose of neoadjuvant combination immunotherapy may suffice to induce effective anti-tumor immunity while reducing the development of severe irAEs.
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