CD206+ tumor-associated macrophages cross-present tumor antigen and drive antitumor immunity
Madhura Modak, Ann-Kathrin Mattes, Daniela Reiss, Wioletta Skronska-Wasek, Rebecca Langlois, Nicolas Sabarth, Renate Konopitzky, Fidel Ramirez, Katharina Lehr, Tobias Mayr, David Kind, Coralie Viollet, Lee Kim Swee, Jutta Petschenka, Karim C. El Kasmi, Elfriede Noessner, Kerstin Kitt, Stefan Pflanz
Madhura Modak, Ann-Kathrin Mattes, Daniela Reiss, Wioletta Skronska-Wasek, Rebecca Langlois, Nicolas Sabarth, Renate Konopitzky, Fidel Ramirez, Katharina Lehr, Tobias Mayr, David Kind, Coralie Viollet, Lee Kim Swee, Jutta Petschenka, Karim C. El Kasmi, Elfriede Noessner, Kerstin Kitt, Stefan Pflanz
View: Text | PDF
Research Article Immunology Oncology

CD206+ tumor-associated macrophages cross-present tumor antigen and drive antitumor immunity

Abstract

In many solid cancers, tumor-associated macrophages (TAM) represent the predominant myeloid cell population. Antigen (Ag) cross-presentation leading to tumor Ag–directed cytotoxic CD8+ T cell responses is crucial for antitumor immunity. However, the role of recruited monocyte-derived macrophages, including TAM, as potential cross-presenting cells is not well understood. Here, we show that primary human as well as mouse CD206+ macrophages are effective in functional cross-presentation of soluble self-Ag and non–self-Ag, including tumor-associated Ag (TAA), as well as viral Ag. To confirm the presence of cross-presenting TAM in vivo, we performed phenotypic and functional analysis of TAM from B16-F10 and CT26 syngeneic tumor models and have identified CD11b+F4/80hiCD206+ TAM to effectively cross-present TAA. We show that CD11b+CD206+ TAM represent the dominant tumor-infiltrating myeloid cell population, expressing a unique cell surface repertoire, promoting Ag cross-presentation and Ag-specific CD8+ T cell activation comparable with cross-presenting CLEC9A+ DCs (cDC1). The presence of cross-presenting CD206+ TAM is associated with reduced tumor burden in mouse syngeneic tumor models and with improved overall survival in cutaneous melanoma patients. Therefore, the demonstration of effective Ag cross-presentation capabilities of CD206+ TAM, including their clinical relevance, expands our understanding of TAM phenotypic diversity and functional versatility.

Authors

Madhura Modak, Ann-Kathrin Mattes, Daniela Reiss, Wioletta Skronska-Wasek, Rebecca Langlois, Nicolas Sabarth, Renate Konopitzky, Fidel Ramirez, Katharina Lehr, Tobias Mayr, David Kind, Coralie Viollet, Lee Kim Swee, Jutta Petschenka, Karim C. El Kasmi, Elfriede Noessner, Kerstin Kitt, Stefan Pflanz

×

Figure 6

CD206+ macrophages can efficiently cross-present soluble CMV pp65 Ag.

Options: View larger image (or click on image) Download as PowerPoint
CD206+ macrophages can efficiently cross-present soluble CMV pp65 Ag. (A...
(A) Dot plots indicate expression of CMV-specific TCR on CD8+ T cells as analyzed by MHC I tetramer staining. CD8+ T cells were stimulated with untreated MDM or MDM pretreated with CMV pp65 short peptide, or they were stimulated with MDM pretreated with CMV pp65 protein. Numbers indicate percentage of CD8+CMV+ T cells. Data are representative of 3 donors. (B–D) Data show cytotoxic activity of differentially stimulated CD8+ T cells, wherein autologous CD8+ T cells were cocultured with untreated (B), CMV pp65 peptide pretreated (C), or CMV pp65 protein pretreated (D) MDM subsets. Bar diagrams show percentage survival of target HCT116 cells, cocultured with differentially stimulated CD8+CMV+ T cells, normalized to HCT116 cells alone. HCT116 cells were either unpulsed or pulsed with CMV pp65 peptide before coculturing with stimulated CD8+ T cells. (B–D) Data show mean ± SEM (n = 3 donors). Unpaired Student’s t test was used. For multiple comparisons, Holm-Šídák test was performed (C). *P < 0.05, **P < 0.01.