New target for colorectal cancer immunotherapy: B7H3/B7H4
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New target for colorectal cancer immunotherapy: B7H3/B7H4
Colorectal cancer (CRC) is one of the most common cancers. In advanced disease, treatment still relies mainly on traditional chemotherapy.
A new generation of cancer treatments, immunotherapy, uses checkpoint inhibitor drugs to target a small subset of known checkpoint proteins, yet therapeutic responses to immune checkpoint inhibition are limited to a small number of colorectal cancers with high microsatellite instability , they are defective in DNA damage repair mechanisms, and microsatellite-stabilized colorectal cancer has 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 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).
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.
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 interference with 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.
Source: Immunity
B7H3 and B7H4 are two B7 family members that interact with unknown receptors expressed by T cells. B7H3 has been shown to inhibit T cell activation, including cytotoxic T cell responses to tumor cells. Blockade or deletion of B7H4, a co-suppressor protein, inhibits tumor growth in mice by increasing CD8+ T cell activation.
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).
Source: Immunity
A series of experiments also 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.
When the gut barrier at the site of tumorigenesis breaks down, bacteria normally present in the gut can suddenly enter surrounding tissues, 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 evade the immune system.
Studies have shown that neutrophil-myeloid-derived immunosuppressive cells integrate microbially derived Toll-like receptor signaling 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 response to microbial signals in the tumor microenvironment, and is amenable to therapeutic targeting.
Although the findings are primarily derived from studies in mice, and the functional relevance of this pathway in human primary colorectal cancer and metastases remains to be further investigated, it provides a promising prospect for future cancer therapy in humans.
References:
1# Kenneth Peuker et al. Microbiota-dependent activation of themyeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumorimmunity in colorectal cancer. Immunity. 2022.
2# Researchers identify new targets for immunotherapy in coloncancer (Source: TU Dresden official website)
New target for colorectal cancer immunotherapy: B7H3/B7H4
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