Release Date: 22-Feb-2023
Over the past ten years, immunotherapy has transformed the way cancer is treated by delivering impressive and long-lasting responses in patients with a wide range of tumor types. It is now considered as the fourth pillar in the treatment of cancer. Through the years, many immunotherapy methods have been brought into the market, but therapies blocking the activities of the immune checkpoint (ICs) proteins have garnered the maximum attention. Immune checkpoints are proteins expressed on the surface of cells and are involved in the regulation of the immune system. They control the initiation, duration and degree of the immune response. In cancer, these proteins are skillfully used by tumors to evade the immune system.
The PD-1 and CTLA-4 are the most sought after immune checkpoints and both of them have several inhibitors designed against them and many of them have entered the market and are being used widely in cancer therapy. Apart from this, another IC known as CD276 was discovered about two decades ago and is theoretically the best IC to target out of all known immune checkpoints. The 316 amino acid long CD276 protein, also known as B7 homolog 3 (B7-H3), is an immunological checkpoint protein with dual immunoregulatory functions as a co-stimulatory/co-inhibitory immunoregulatory protein. It was initially reproduced in 2001 using a human dendritic cell-derived cDNA library.
The extracellular domain of the human B7-H3 protein determines its two isoforms, 4IgB7-H3 and 2IgB7-H3. Both variants have domains that are similar to IgV and IgC. The IgV domain contains the FG loop, which is crucial for its immunologic function and is found in all immunological checkpoint proteins. Despite the protein's ubiquitous mRNA presence, not all cells and organs express it. Monocytes, B, T, and NK cells do not naturally express B7-H3, but antigen-presenting cells can be induced to do so at low levels. The highest expression, however, is found in cancer tissues, and multiple studies have demonstrated a correlation between the overexpression of B7-H3 and tumor aggressiveness and a bad prognosis. B7-H3 is a part of several pathways that control the cell cycle, epithelial-mesenchymal transition, cell growth, apoptosis, invasion, differentiation and autophagy.
Further, this also helps tumors in developing resistance against some common chemotherapeutics such as Paclitaxel. Its involvement in chemoresistance and tumor aggressiveness makes it unique when compared to its counterparts. To establish these effects, the protein interacts with several proteins and enzymes including PDK1, Nrf2, PRX3, JAK3 and STAT3. In reference to cancer, other immune checkpoints are mainly involved in suppressing the immune response but do not affect carcinogenesis or the treatment regimen, which gives B7-H3 an edge over them and evidences its potential as a target for cancer immunotherapy.
Due to its extensive roles in cancer despite being simply an immunological checkpoint, the discovery of B7-H3 and its actions caused a stir in the scientific community. These demonstrate that despite the years of effort put into characterizing immunological checkpoints, there is still much to learn, which calls for additional study of these proteins. The diverse functions of B7-H3 in relation to cancer make it a desirable target for the creation of medicines. Given that it is extensively expressed in cancer tumors and barely detectable in healthy tissues, drugs that target this protein are likely to be extremely cancer cell-specific. The development of drugs that can prevent it from interacting with its receptors and other enzymes has received a lot of attention. Antibodies targeting the FG loop have been designed to induce inhibitory effects on the protein.
The functioning of CD276 is challenging to understand. Even though a substantial amount of progress has been accomplished over the last 20 years, more study is still required. The control of CD276 expression is tightly correlated with immune evasion, invasion, and metastasis of tumors. Because of CD276's elevated expression levels in numerous malignancies and its low expression in a variety of healthy tissues, it has emerged as another hot topic in the cancer RandD domain. Overall, CD276 has a lot of potential as an immunotherapeutic target, but more research and clinical trials are needed to verify its clinical significance. Its unusual functions have also shown that perhaps what we currently know about certain ICs is everything and there are more characters that are possibly hidden which need to be uncovered to make progress in immunotherapy and the science field in general.