Chinese scholars have made progress in remodeling antibody characteristics in immunotherapy

Figure Immune checkpoint blocking therapy remodeling antibody characteristics induces tumor immune evasion

With the funding of the National Natural Science Foundation of China (grant numbers: 82025016, 31830025 and 81901585), Professor Kwong Dongming's team of Sun Yat-sen University has made progress
in remodeling antibody characteristics in immunotherapy 。 The findings are based on "Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular.
" carcinoma", published
in the journal Immunity.
Link to paper: https://doi.
org/10.
1016/j.
immuni.
2022.
11.
014
.

Immune checkpoint blockade (ICB) shows good application prospects
in the treatment of a variety of solid tumors by restoring and enhancing the anti-tumor function of effector T cells.
However, the number of cancer patients who can benefit from ICB therapy is currently very limited, which is due to ICB therapy activating the immune response while initiating a negative feedback regulatory pathway, which in turn leads to secondary drug
resistance.
Elucidating the negative feedback mechanism triggered by ICB therapy will not only reveal the causes of ICB treatment resistance/resistance, but also help develop novel combination strategies
for tumor immunotherapy.
In solid tumors such as liver cancer, killer T cells and plasma cells are often co-localized to the inflammatory region of the tumor, but little is known whether ICB therapy affects and regulates the response characteristics of antibodies
.

The research team used tandem mass spectrometry to detect the N-linked glycosylation modification spectrum of IgG antibodies in surgical specimens of liver cancer patients under different treatment regimens, and found that sialylated IgG antibodies were selectively enriched in samples of patients receiving αPD-1 treatment.
Under ICB treatment, activated effector T cells stimulated hepatoma cells to secrete sialyltransferase in an γ interferon-dependent manner, thereby catalyzing the sialylation modification of IgG antibodies.
Enhanced levels of sialylated IgG antibodies reflect the degree of activation of effector T cells within tumors; The main target cells of sialylated IgG antibody are DC-SIGN⁺ macrophages in liver cancer, and after DC-SIGN interacts with sialylated modified IgG antibody, it activates downstream Raf-1 signaling and upregulates ATF3 expression, inactivating the cGAS-STING pathway, thereby eliminating the anti-tumor immune effect mediated by type I interferon.
Blocking the sialylation modification of IgG antibody can significantly enhance the anti-tumor immune response induced by ICB therapy and promote tumor regression (Figure).

This study reveals a new mechanism of negative feedback of ICB treatment resistance, which can provide a new strategy for enhancing the efficiency of ICB therapy by blocking the negative feedback pathway induced by sialylated IgG antibodies.
The degree of sialylation modification of IgG antibody can be used as a biological marker to provide a basis
for judging the effectiveness of ICB therapy.