February 9, 2023

Examining the Immune Suppressive Role of Neutrophils in Human Colorectal Cancer

2nd Call, iDoc

Short Summary

High T cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T cell responses in CRC could inspire novel therapeutic approaches to achieve broader immunotherapy responsiveness. Here we investigated T cell suppressive properties of different myeloid blood lineages in an inducible colon tumor mouse model and primary human patient samples. The most potent inhibitors of T cell activity were tumor-infiltrating neutrophils. Our studies indicate that T cell suppression is mediated by neutrophil-secreted metalloproteinase activation of latent TGFβ. The cytokine TGF if present in the tumor microenvironment has a strong immune suppressive activity. Thus, interfering with the recruitment of neutrophils into the tumor microenvironment or inhibiting their proteolytic activation of the inactive TGF- precursor protein might be beneficial for CRC patients.

Goals

The overall goal of this research proposal is to identify mechanisms within the CRC tumor microenvironment that may contribute to tumor immune suppression. The work performed here aims to investigate how myeloid cells within the CRC tumor microenvironment is involved in inhibiting T cell immunity against cancer cells.

Significance

Our study suggests that combination therapy of CXCR2, TGFBR or MMP9 inhibitors with immune checkpoint blockade could broaden immunotherapy responsiveness in CRC patients, especially in those with pervasive neutrophil infiltration and TGFβ activity.

Background

Colorectal cancer (CRC) is one of the major forms of cancer and one of the leading causes of death in adults. Although the sequence of events of the mutational activation of oncogenes and mutational loss of tumor suppressors is rather well characterized in human CRC, it is clear that the progression of the disease is not only a cell autonomous process. Progression is also affected by extrinsic factors such as the tumor microenvironment, including the tumor infiltrating immune cells. In this context, it has been shown that CRC patients with high T cell infiltration have a rather good prognosis and a better overall survival compared to patients with low T cell infiltration, suggesting that immune-surveillance might be an important component of CRC progression. This led to clinical trials administering immune checkpoint inhibitors aiming to initiate anti-tumor T cell responses. Unfortunately, they were largely unsuccessful. This unresponsiveness of the vast majority of CRC patients to immune checkpoint inhibitors suggests that additional and currently unknown factors contribute to the inhibition of efficient anti-tumor T cell responses.