Immune Checkpoint Blockade Improves Chemotherapy in the PyMT Mammary Carcinoma Mouse Model

Frontiers in Oncology

Bernhard Brüne¹  Catherine Olesch²  Evelyn Sirait-Fischer²  Arnaud Huard²  Tobias Schmid²  Annika F. Fink²  Matthias Berkefeld²  Andreas Weigert⁴  Kazuhiko Takeda⁵ 

[1] Branch for Translational Medicine and Pharmacology TMP of the Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Frankfurt, Germany;Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany;Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany;German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany;Research Center of Oncology, ONO Pharmaceutical Co., LTD, Osaka, Japan;

关键词: cancer;    immunotherapy;    chemotherapy;    immune checkpoint;    cytotoxic lymphocytes;   

DOI  :  10.3389/fonc.2020.01771

来源: DOAJ

【 摘 要 】

Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.

【 授权许可】

Unknown