Abstract 4059: Vaccination causes a clear subtype shifting of tumor infiltrate Treg in mouse breast cancer homografts

Abstract

Tumor-infiltrating lymphocytes (TIL), including CD8+ TIL-Teff (effector T-cells) and TIL-Treg (regulatory T-cells with immune suppression on self-restricted Teff), are believed to play a significant, but somewhat conflicting, role in the cancer prognosis and sensitivity to immune-oncology (I/O) treatments, including immune checkpoint inhibitors (ICI). Forkhead box P3 (FoxP3+) has long been considered a key marker of Treg while recent research has indicated significant heterogeneity of Treg with different levels of FoxP3 and the associated functional variations. The heterogeneity may explain some of the conflicting observations. The influence of the Treg heterogeneity on ICI treatment has yet to be investigated. We have previously created a mouse tumor homograft, mBR6004, by orthotopic-implanting breast adenocarcinoma spontaneously developed in MMTV-PyVT transgenic mice (GEMM) to the syngeneic FVB/N mice. The homograft has the similar growth, metastasis and histopathology as seen for the original GEMM tumors, and it responds to the CTLA-4 but not to the PD1/PDL1 inhibitors. Further, we also found that a prior vaccination treatment seemed to potentially render the tumor sensitive to PD1/PD-L1 inhibitors with increased CD8+ TIL in the treated tumors. To explore the underlying mechanism of vaccination, we are performing extensive immunophenotyping of TILs in the vaccinated tumors. Interestingly, our analysis clearly displayed a drastic shift of TIL-Treg from FoxP3lo to FoxP3hi population in the tumors with the prior vaccination as compared to the tumor without vaccination, which likely corresponds to the reported naïve FoxP3lo Treg and FoxP3hi effector Treg (eTreg). This FoxP3hi -shifted Treg is also largely absent in peripheral blood, even in the vaccinated mice, consistently to those seen in patients. Our data seem to suggest that the TIL-eTreg status, not naïve Treg, could play a critical role in tumor response to the checkpoint inhibitor treatment, and that the methods, such as vaccination to change TIL-eTreg, could be an important strategy to enhance checkpoint inhibitor treatment. In addition, the elucidation of TIL-Treg in animal model could also greatly help to investigate I/O mechanisms in the experimental settings.

Citation Format: Xiaoyu AN, Davy Xuesong Ouyang, Jinping Liu, Li Chen, Henry Qixiang Li. Vaccination causes a clear subtype shifting of tumor infiltrate Treg in mouse breast cancer homografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4059.