Immunological differences between colorectal cancer and normal mucosa uncover a prognostically relevant immune cell profile

Abstract

T cells in colorectal cancer (CRC) are associated with improved survival. However, checkpoint immunotherapies antagonizing the suppression of these cells are ineffective in the great majority of patients. To better understand the immune cell regulation in CRC, we compared tumor-associated T lymphocytes and macrophages to the immune cell infiltrate of normal mucosa. Human colorectal tumor specimen and tumor-distant normal mucosa tissues of the same patients were collected. Phenotypes and functionality of tissue-derived T cells and macrophages were characterized using immunohistochemistry, RNA in situ hybridization, and multiparameter flow cytometry. CRC contained significantly higher numbers of potentially immunosuppressive CD39 and Helios-expressing regulatory T cells in comparison to normal mucosa. Surprisingly, we found a concomitant increase of pro-inflammatory IFNγ -producing T cells. PD-L1+ stromal cells were decreased in the tumor tissue. Macrophages in the tumor compared to tumor-distant normal tissue appear to have an altered phenotype, identified by HLA-DR, CD14, CX3CR1, and CD64, and tolerogenic CD206+ macrophages are quantitatively reduced. The prognostic effect of these observed differences between distant mucosa and tumor tissue on the overall survival was examined using gene expression data of 298 CRC patients. The combined gene expression of increased FOXP3, IFNγ, CD14, and decreased CD206 correlated with a poor prognosis in CRC patients. These data reveal that the CRC microenvironment promotes the coexistence of seemingly antagonistic suppressive and pro-inflammatory immune responses and might provide an explanation why a blockade of the PD1/PD-L1 axis is ineffective in CRC. This should be taken into account when designing novel treatment strategies.

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

“…Tregs are involved inter alia in the suppression of inflammation mediated by effector T cells by several mechanisms including the release of TGF-β and IL-10 (44). In CRC, the average amount of Tregs was found to be increased in the blood of patients relative to healthy volunteers, and in the tumor relative to the adjacent non-tumor tissue (45,46). Moreover, several studies demonstrated that Tregs derived from both blood and tumor of CRC patients were able to suppress the proliferation of autologous CD4 and CD8 T cells (47,48), and that the frequency of Tregs was negatively correlated with the expression of IFN-γ and IL-2 in the tumors (49).…”

The role of neutrophil death in chronic inflammation and cancer

“…In contrast, autoimmune diseases and cancer are frequently associated with reduced neutrophil apoptosis 45 . Many solid tumors including colorectal cancer, lung cancer and breast cancer are characterized by a high neutrophil infiltration [46][47][48] . However, its predictive value differs between cancer types 8 .…”

Exploration of the role of tumor mutation burden in clinical significance, immunotherapy response predictor and immune cell infiltration in colon cancer

“…Several studies demonstrated that Tregs negatively correlated with prognosis in CRC 47,48 . Interestingly, Tregs may suppress the proliferation of immunoreactive T cells, such as CD8T cell 49 .…”