Abstract
IntroductionAlthough systemic T-cell responses against tumor antigens and tumor infiltration by T cells have been investigated in colorectal cancer (CRC), the initiation of spontaneous immune responses in situ is not well understood. Macrophages and dendritic cells (DC) play an important role as a link between innate and adaptive immune response. The aim of the present study was to analyze macrophage and DC infiltration in CRC and to investigate whether there is a correlation to systemic T-cell response, regulatory T cell (Treg) infiltration, and survival.MethodsImmunohistological staining was performed with nine markers for macrophages and DC (CD68, CD163, S100, CD11c, CD208, CD209, CD123, CD1a, Langerin) in 40 colorectal cancer samples from patients, in whom the state of systemic T-cell responses against tumor-associated antigens (TAA) and Treg infiltration had previously been determined.ResultsAll specimens contained cells positive for CD68, CD163, S100 and CD1a in epithelial tumor tissue and tumor stroma. Only a very few (less than median 3/HPF) CD123+, CD1a+, CD11c+, CD 208+, CD209+, or Langerin+ cells were detected in the specimens. Overall, we found a trend towards increased infiltration by S100-positive DC and a significantly increased number of stromal S100-positive DC in patients without T-cell response. There was an increase of stromal S100 DC and CD163 macrophages in limited disease (S100: 11.1/HPF vs. 7.3/HPF, p = 0.046; CD163: 11.0/HPF vs. 8.1/HPF, p = 0.06). We found a significant, positive correlation between S100-positive DC and FOXP3-positive Tregs. Survival in patients with high DC infiltration was significantly better than that in those with low DC infiltration (p < 0.05). Furthermore, we found a trend towards better survival for increased infiltration with CD163-positive macrophages (p = 0.07).ConclusionThe present in situ study adds new data to the discussion on the interaction between the innate and adoptive immune system. Our data strongly support the hypothesis that tumor-infiltrating DC are a key factor at the interface between innate and adaptive immune response in malignant disease. Tumor infiltrating S100-positive DC show an inverse relationship with the systemic antigen-specific T-cell response, a positive correlation with regulatory T cells, and a positive association with survival in CRC. These data put tumor-infiltrating DC at the center of the relevant immune response in CRC.
Highlights
Systemic T-cell responses against tumor antigens and tumor infiltration by T cells have been investigated in colorectal cancer (CRC), the initiation of spontaneous immune responses in situ is not well understood
We showed that the average regulatory T cell (Treg) infiltration rate in the tumor was slightly higher in patients without systemic tumor-associated antigens (TAA)-specific T-cell response and that Treg infiltration in the tumor stroma was significantly higher in limited disease than in metastatic CRC [23]
The aim of the present study was to analyze colorectal cancer infiltration by macrophages and dendritic cells of various phenotypes in situ and to test whether there is a correlation to a systemic TAA-specific T-cell response, Immunohistochemistry and microscopic analysis For immunostaining, 4 μm thick sections were cut, deparaffinized, and subjected to heat-induced epitope retrieval before incubation with antibodies
Summary
Systemic T-cell responses against tumor antigens and tumor infiltration by T cells have been investigated in colorectal cancer (CRC), the initiation of spontaneous immune responses in situ is not well understood. The aim of the present study was to analyze macrophage and DC infiltration in CRC and to investigate whether there is a correlation to systemic T-cell response, regulatory T cell (Treg) infiltration, and survival. Systemic T-cell responses against tumor antigens and tumor-infiltrating T cells have been analyzed in detail in CRC. Patients with CRC – as well as those with other malignant diseases – are able to mount an antigen-specific T cell response without prior immunotherapy [7,8]. In a first analysis with a limited number of colorectal cancer patients, no survival benefit was found for patients with peripheral TAA-directed T-cell responses [9]. Limited antitumor activity of spontaneous antigen-specific T cells at a clinical level in CRC patients may be due to multiple factors
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