A new target for colorectal cancer immunotherapy: B7H3/B7H4

A new generation of cancer treatment, immunotherapy, uses checkpoint inhibitor drugs to target a small subset of known checkpoint proteins, but therapeutic response to immune checkpoint inhibition is limited to a small number of colorectal cancers with high microsatellite instability , they are defective in DNA damage repair mechanisms, and microsatellite-stabilized colorectal cancers have no objective response

This piqued scientists' curiosity: Are there other checkpoint proteins that could be more promising targets for colorectal cancer immunotherapy?

On March 31, researchers at the Technical University of Dresden published their latest findings in the journal Immunology, where they identified the proteins B7H3 and B7H4 as promising candidates for a new immunotherapy against colorectal cancer.

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

Because myeloid cells express a functional calcineurin NFAT axis that can be activated by Toll-like receptor agonists, the researchers explored the role of this pathway in intestinal tumor development

Antibody-mediated blockade or gene deletion of this pathway member inhibited tumor development and promoted the regression of metastatic colorectal cancer in mouse experiments, suggesting that interference with this pathway member activates CD8+ T cell-dependent anti-tumor Tumor immunity and durable disease control

Specifically, myeloid tumor-infiltrating cells show microbe-dependent activation of calcineurin and NFAT, which orchestrate an immunosuppressive cross-talk network in microsatellite-stabilized colorectal cancer that is dependent on myeloid IL-6 and correlated with STAT3-dependent expression of colorectal cancer cell co-suppressors 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 is almost exclusively derived from epithelial tumor cells rather than tumor-infiltrating immune cells

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

The team also noted that disruption of the gut barrier is a key factor in the development of colorectal cancer, increasing its ability to fight off immune cells

When the gut barrier at the site of a tumor breaks down, bacteria normally present in the gut can suddenly enter the surrounding tissue, which is considered an important early event in the development of colorectal cancer

Now, the team can show that escape of these bacteria is the initial trigger for colorectal cancer cells to escape the immune system

Studies have shown that neutrophil-myeloid-derived immunosuppressive cells integrate microbial-derived toll-like receptor signaling pathways to control the tumor-promoting effects of myeloid calcineurin

Collectively, this study uncovers a pathway that inhibits microsatellite-stabilized CD8+ T cell responses in colorectal cancer, is activated in the tumor microenvironment in response to microbial signals, and is suitable for therapeutic targeting

Although these findings are primarily derived from studies in mice and the functional relevance of this pathway in human primary colorectal cancer and metastasis remains to be further investigated, it offers a promising prospect for future human cancer therapy

1# Kenneth Peuker et al.

2# Researchers identify new targets for immunotherapy in coloncancer (Source: TU Dresden official website)