Abstract 13P
Background
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and accounts for 40% of breast cancer deaths. Currently, surgery and chemotherapy are standard therapy in TNBC, whereas immunotherapies often fail due to a cold tumor microenvironment (TME), which is mainly generated by tumor associated macrophages (TAMs). Importantly, immunosuppressive M2-like TAMs are associated with worse outcome in TNBC patients. Cytokines like IL-10 and TGFβ induce M2-like TAMs, which inhibit the adaptive immune response and promote tumor growth, migration, and vascularization. In contrast, M1-like macrophages induce an anti-tumor immune response and tumor cell death. Thus, we aim to develop an adoptive cell therapy employing macrophages that are polarized towards a M1-like phenotype by the immunosuppressive cytokines, which will generate an inflamed TME.
Methods
To achieve M1 polarization in a M2-inducing TME, we genetically modified macrophages to express a chimeric cytokine receptor (ChCR), which will induce an M1 signaling upon stimulation with M2 inducing cytokines. Here, we evaluated two ChCR variants activated by IL-10 and TGFβ, respectively. We transduced monocytes to express the ChCR using lentiviruses. Upon differentiation to macrophages, we assessed M1 polarization by analyzing surface marker expression and the secretome. Moreover, we assessed their effect on TNBC cell line viability.
Results
We could successfully transduce macrophages at 80% and confirmed ChCR expression and M1 signaling. Furthermore, we could show that stimulation of ChCR macrophages by IL-10 or TGFβ switches them towards an M1-like phenotype, as analyzed by surface marker expression and IP-10 secretion. Moreover, we found that the viability of TNBC cell lines was reduced upon treatment with supernatants of TGFβ or IL-10 stimulated ChCR macrophages.
Conclusions
We could show that we can engineer macrophages to switch towards an M1-like phenotype in an M2-inducing environment. Thus, ChCR macrophages represent a promising strategy to disrupt the immunosuppressive TME. Currently, we are assessing the effect of ChCR macrophages on immune activation in vitro and their phenotype in TNBC co-cultures.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Gebauer Stiftung, Lotte und Adolf Hotz-Sprenger-Stiftung, Claudia von Schilling, Foundation for Breast Cancer Research, OPO-Stiftung, Stiftung zur Krebsbekämpfung, Alfred und Anneliese Sutter-Stöttner Stiftung, Dr. Arnold U. und Susanne, Huggenberger-Bischoff Stiftung, Novartis Foundation for Medical-Biological Research, UZH Bio & MedTech Entrepreneur Fellowship, UZH Postdoc Grant.
Disclosure
R.F. Speck: Other, Personal and Institutional, Other, Inventor of pending patent EP 22/215498 related to project: University of Zurich. S. Bredl: Financial Interests, Personal and Institutional, Other, Inventor of pending patent EP 22/215498 related to project: University of Zurich. All other authors have declared no conflicts of interest.
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