RT Journal Article
SR Electronic
T1 Synergy of chemotherapy and macrophage depletion leads to T cell memory activation and durable triple negative breast cancer regression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.22.432300
DO 10.1101/2021.02.22.432300
A1 Swarnima Singh
A1 Nigel Lee
A1 Igor Bado
A1 Clark Hamor
A1 Licheng Zhang
A1 Sergio Aguirre
A1 Jingyuan Hu
A1 Yichao Shen
A1 Yitian Xu
A1 Yang Gao
A1 Diego Pedroza
A1 Na Zhao
A1 Shu-Hsia Chen
A1 Ying-Wooi Wan
A1 Zhandong Liu
A1 Jeffrey T. Chang
A1 Daniel Hollern
A1 Charles M. Perou
A1 Xiang H.F. Zhang
A1 Jeffrey M. Rosen
YR 2021
UL http://biorxiv.org/content/early/2021/02/22/2021.02.22.432300.abstract
AB Immunosuppressive elements within the tumor microenvironment such as Tumor Associated Macrophages (TAMs) can present a barrier to successful anti-tumor responses by cytolytic T cells. We employed preclinical syngeneic p53 null mouse models of TNBC to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose chemotherapy coupled with the pharmacologic inhibition of TAMs. Combination therapy was used to successfully treat several highly aggressive, claudin-low murine mammary tumors and lung metastasis. Long-term responders developed tertiary lymphoid structures co-infiltrated by T and B cells at the treatment site. Mechanistically, CD86+ antigen-experienced T cells exhibited polyclonal expansion and resulted in exceptional responses upon tumor rechallenge. Combination treatment also eliminated lung metastases. High dimensional transcriptomic data for CD45+ immune cells lead to the identification of an aberrant developmental trajectory for TAMs that were resistant to treatment. Signatures derived from these TAM populations were predictive of patient response to our therapy. This study illustrates the complexity of tumor infiltrating myeloid cells and highlights the importance of personalized immuno-genomics to inform therapeutic regimens.Statement of significance Triple negative breast cancer is aggressive and hard to treat as it has no targeted therapies. Targeting immunosuppressive macrophages in murine models of TNBC alongside an immunostimulatory chemotherapy achieved long-term primary tumor regression in multiple murine mouse models. The transcriptomic heterogeneity between TAMs in phenotypically similar models can be used to uncover future therapeutic targets. Additionally, signatures derived from these murine models can be applied to TNBC patient data sets to predict cohorts of patients that will respond to the treatment strategy.Competing Interest StatementThe authors have declared no competing interest.