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posted on 2023-10-04, 07:20 authored by Merel van Gogh, Jesus F. Glaus Garzon, Dilara Sahin, Lucia Knopfova, Petr Benes, Onur Boyman, Igor Jurisica, Lubor Borsig Early c-Myb upregulation is crucial for control of tumor growth. A, Experimental setup. C57BL/6J mice were subcutaneously injected with MC38T/O cells and fed Ctrl or Dox chow. For two groups, chow is switched at day 14 for the rest of the experiment, Dox→Ctrl (D→C) or Ctrl→Dox (C→D). B–D, Tumor growth curves, final tumor weight, representative pictures (B); flow cytometry analysis (C); and Bio-plex analysis (D) of indicated groups are shown. Heat maps are shown of representative samples. E, Flow cytometry analysis of subcutaneous MC38T/O tumors at day 14. Flow cytometry analysis for CD8+ T cells (CD45+CD11b−CD3e+CD8+) are represented as number of cells per gram of tumor tissue (C, E). CD8+PD1+/perforin+/granzymeB+ populations are represented as percentage of total CD8+ T cells (C, E). F, Long-term tumor growth was assessed in C57BL/6J mice subcutaneously injected with MC38T/O cells and fed Ctrl or Dox chow for the duration of the experiment; or Dox chow for the first 14 days and subsequently switched to Ctrl chow for the rest of the experiment (D → C). n = 5–6 (B), n = 4 (C), n = 3–4 (D), n = 8–10 (E), n = 7–8 (F) mice per group. Data are presented as mean values ± SEM. Two-way ANOVA was used for comparing tumor growth curves (B, F). One-way ANOVA with Kruskal–Wallis posttest was used (C–E) for statistical analysis. *, P < 0.05; **, P < 0.01.
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
Swiss Cancer Research Foundation (Swiss Cancer Research)
History
ARTICLE ABSTRACT
The transcription factor c-Myb is overexpressed in many different types of solid tumors, including colorectal cancer. However, its exact role in tumorigenesis is unclear. In this study, we show that tumor-intrinsic c-Myb expression in mouse models of colon cancer and melanoma suppresses tumor growth. Although no differences in proliferation, apoptosis, and angiogenesis of tumors were evident in tumors with distinct levels of c-Myb expression, we observed changes in intratumoral immune cell infiltrates. MC38 tumors with upregulated c-Myb expression showed increased numbers of CD103+ dendritic cells and eosinophils, but decreased tumor-associated macrophages (TAM). Concomitantly, an increase in the number of activated cytotoxic CD8+ T cells upon c-Myb upregulation was observed, which correlated with a pro-inflammatory tumor microenvironment and increased numbers of M1 polarized TAMs. Mechanistically, c-Myb upregulation in immunogenic MC38 colon cancer cells resulted in enhanced expression of immunomodulatory genes, including those encoding β2-microglobulin and IFNβ, and decreased expression of the gene encoding the chemokine receptor CCR2. The increased numbers of activated cytotoxic CD8+ T cells contributed to tumor growth attenuation. In poorly immunogenic CT26, LLC, and B16-BL6 tumor cells, c-Myb upregulation did not affect the immunomodulatory gene expression. Despite this, c-Myb upregulation led to reduced B16-BL6 tumor growth but it did not affect tumor growth of CT26 and LLC tumors. Altogether, we postulate that c-Myb functions as a tumor suppressor in a tumor cell–type specific manner and modulates antitumor immunity.
