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2024

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Nanjing University Wei Jia team reported a targeted oncogenic fusion gene CLDN18-ARHGAP in gastric cancer immunotherapy!

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Gastric cancer (GC), the sixth largest cancer type in the world and the third largest cause of death, is considered to be highly heterogeneous both histologically and genetically.Despite the clinical progress of anti-HER2 targeted therapy and anti-PD-1/PD-L1 immunotherapy, there is still a lack of specific treatment for gastric cancer.

August 20, 2024, Nanjing UniversityWei JiaTeamInEMBO Molecular MedicinePublished online entitled“Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer”The research paper,The study reported aTargeted carcinogenesis in gastric cancerfusion geneImmunotherapy for CLDN18-ARHGAP.

The study found that a gastric cancer oncodriver gene CLDN18-ARHGAP a fusion gene, in 87 cases of gastric cancer patients, the detection rate was 9%(8/87). Preparation of immunogenic peptides specifically targeting CLDN18-ARHGAP fusion genes to induce neoantigen-reactive T cells with specific and powerful anti-tumor capacity in both in vitro co-culture models and in vivo xenograft gastric cancer models. In addition to the immunogenic potential, CLDN18-ARHGAP fusion genes were also found to potentiate immunosuppression by inducing a regulatory T(Treg) cell-enriched microenvironment. Mechanically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production by gastric cancer cells in favor of Treg cell survival. In addition, PI3K inhibition can effectively reverse the up-regulation of Treg cells, enhance the anti-tumor cytotoxicity of new antigen-reactive T cells in vitro, and inhibit tumor growth in xenograft gastric cancer models.The study found that the CLDN18-ARHGAP fusion gene is a key source of immunogenic neoepitopes and a key regulator of the tumor immune microenvironment, which can be used for the immunotherapy of oncogenic fusion.

Innovative therapies targeting neoantigens, including neoantigen vaccines and neoantigen-reactive T cell (NRT) therapies, have led to revolutionary breakthroughs in the treatment of a variety of solid tumors.Multiple mouse and human studies have provided evidence for effective treatments based on neoantigens, where neoantigens derived from driver mutations tend to be more tumor-specific, immunogenic and tumor-presenting, and more likely to elicit a better immune response.We have reported the treatment effect of a patient with metastatic colorectal cancer. After the infusion of tumor infiltrating lymphocytes specifically targeting KRASG12D mutations, the objective regression of lung metastasis was observed. In addition, the team has constructed a driver mutation derived from the new antigen peptide library, for a variety of refractory cancer common hot spot mutations, based on the construction of the new antigen vaccine and NRT therapy has a significant and long-lasting anti-tumor effect.However, current neoantigen-based strategies are mainly derived from single nucleotide variations (SNVs), insertions or deletions (INDEL), whereas gastric cancer lacks hotspot mutations in SNV or INDEL. Therefore, there is still a need to further explore alternative targets for the application of neoantigen therapy in gastric cancer.

In addition to SNVs and INDELs, neoantigens derived from fusion genes formed by structural chromosomal variations (SVs) tend to have higher immunogenicity and therapeutic potential in cancers lacking SNVs or INDELs hotspot mutations.To date, multiple neoantigens derived from fusion genes, such as BCR-ABL in chronic myeloid leukemia, tumor-specific translocation breakpoints in Ewing's sarcoma, and MYB-NFIB in head and neck cancer, can induce robust antigen-specific responses in patient autologous T cells.In recent years, advances in high-throughput sequencing have provided a comprehensive map of the gastric cancer genome, greatly facilitating the detection of novel gene mutations. In 2014, for the first time, the Cancer Genome Atlas (TCGA) identified CLDN18-ARHGAP fusion genes in 4% of gastric cancers. In 2018, scholars found that the common proportion of CLDN18-ARHGAP fusion genes in gastric signet ring cell carcinoma (SRCC) is as high as 25%, and confirmed that CLDN18-ARHGAP fusion genes are carcinogenic drivers of gastric cancer, and CLDN18-ARHGAP fusion patients are associated with poor survival outcomes and chemotherapy resistance. However, it is not clear whether it is a potential therapeutic target based on neoantigens.

The inhibitory tumor immune microenvironment (TIME) is considered to be a key factor affecting the efficacy of immunotherapy in a variety of solid tumors. Recent studies have shown that the oncogenic signaling pathways initiated or activated by driver gene mutations contribute to a large extent to the formation of inhibitory TIME. Mutation, loss, or amplification of driver genes such as PIK3CA, PTEN, or AKT can aberrantly activate PI3K-AKT-mTOR signaling, promoting the accumulation of regulatory T(Treg) cells and tumor-associated macrophages (TAMs) in the local tumor microenvironment and immunosuppression.Nevertheless, it remains unclear whether CLDN18-ARHGAP fusion genes can serve as driver gene mutations that modulate the immunosuppressive effects of TIME.
The study reported that CLDN18-ARHGAP fusion occurred in 9% of Chinese gastric cancer patients and could produce immunogenic neoantigenic peptides that induced strong specific antitumor cytotoxicity in NRT cells. In addition, the authors demonstrated that gastric cancer cells with CLDN18-ARHGAP fusion increased free fatty acid (FFA) production by activating the PI3K-AKT-mTOR/FAS signaling pathway, thereby promoting the infiltration and survival of Treg cells within TIME.Finally, based on the immunogenic and immunomodulatory properties of CLDN18-ARHGAP fusion proteins, this study proposes NRT cell infusion or PI3K inhibition as novel interventions for gastric cancer immunotherapy.

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