Immunity: B7H3/B7H4 is expected to become a new target for colorectal cancer immunotherapy

Colorectal cancer (CRC) is one of the most common cancers

On March 31, researchers at the Technical University of Dresden published their latest findings in Immunity, in which they identified the proteins B7H3 and B7H4, promising targets for new immunotherapies against colorectal cancer, and highlighted gut bacteria Central role in the development of colorectal cancer

The research team has previously demonstrated that bacterial sensing of intestinal tumor cells promotes tumor growth through intracellular activation of calcineurin, as well as calcineurin-dependent activation of activated T cell nuclear transcription factor (NFAT)

In mouse experiments, antibody-mediated blockade or genetic deletion of members of this pathway inhibited tumor development and promoted regression of metastatic colorectal cancers, demonstrating that perturbation of members of this pathway activates CD8 ⁺ T cell-dependent Antitumor immunity and durable disease control

Specifically, myeloid tumor-infiltrating cells exhibit microbiota-dependent activation of calcineurin and NFAT, which orchestrate an immunosuppressive crosstalk network in microsatellite-stabilized colorectal cancer that is dependent on myeloid IL-6 and correlated with STAT3-dependent expression of colorectal cancer cell co-repressors B7H3 and B7H4, which in turn inhibited CD8 ⁺ T cell responses

B7H3 and B7H4 are two B7 family members that interact with unknown receptors expressed by T cells

The study also showed that the expression of B7H3 and B7H4 was almost exclusively derived from epithelial tumor cells rather than tumor-infiltrating immune cells (Panel C, lower panel, which was confirmed by immunohistochemistry (Panel B, lower panel)

Source: Immunity

A series of experiments further verified that B7H3 and B7H4 indeed function as checkpoint proteins

In addition, the research team pointed out that breaking the intestinal barrier is a key factor in promoting colorectal cancer to improve its ability to resist immune cells

Corresponding author Professor Sebastian Zeissig said: "Our findings provide a new link between the microbiota and tumor growth in colorectal cancer

Collectively, this study uncovers a pathway that inhibits microsatellite-stabilized CD8 ⁺

Prof Zeissig said: "Our analysis of human samples showed that B7H3 and B7H4 are also present in human colorectal cancer cells and that their presence is associated with poorer prognosis in patients with colorectal cancer

Original source:

Kenneth Peuker et al.