Gold complex 2G and its role in immunogenic cell death and antitumor immunity in malignant pleural mesothelioma.

Abstract

e20095 Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure, characterized by an immunologically cold microenvironment with minimal immune cell infiltration. This cold tumor milieu poses significant challenges for effective treatment. Recent approvals of PD-1/PD-L1 inhibitors highlight the critical need to convert cold tumors into "hot" tumors to improve the efficacy of immunotherapy. Additionally, the activation of immunogenic cell death (ICD) represents a promising strategy, provoking a robust immune response that enables the immune system to target residual tumor cells. Methods: BALB/c female mice (6 mice per group) were injected subcutaneously with AB12 cells at a concentration of 1 × 10⁷ cells/mL on the right flank. Once tumors reached approximately 100-200 mm³, systemic treatment was initiated through intraperitoneal injections on Days 19, 21, and 23. The gold-based drug 2G was administered at a dosage of 3.5 mg/kg. The positive control group received a combination of cisplatin (1 mg/kg) and pemetrexed (5 mg/kg). Tumor dimensions were measured using calipers, and tumor volume was calculated. In a tumor vaccination assay, AB12 cells were treated with 2G to induce 65-75% cell death after being grown for 16 hours. Following this, the cells were washed and adjusted to 3 × 10⁵ cells per 100 μL for injection into BALB/c female mice (8 mice per group). The mice were subsequently rechallenged with the same amount of tumor cells, and tumor growth was monitored daily. Results: In a vaccination assay, seven of the eight mice vaccinated with 2G remained tumor-free for 164 days (5.5 months), and four of the eight remained tumor-free for 210 days (7 months), indicating that 2G induced a robust and durable antitumor adaptive immune response in immunocompetent mice. IHC staining of tumor samples revealed high expression of ICD markers, particularly IBA1. Additionally, it was noted that there was no toxicity to the livers and kidneys of the treated mice. Furthermore, in the tumor allograft model, 2G significantly inhibited tumor growth more effectively than the standard of care with cisplatin and pemetrexed. The size of tumors treated with 2G was approximately 2.8 times smaller than those treated with the cisplatin-pemetrexed combination. Conclusions: The gold complex 2G has demonstrated the ability to induce immunogenic cell death (ICD) in preclinical models, showing greater efficiency than standard treatment options. By converting malignant pleural mesothelioma from a cold tumor into a hot tumor, the gold complex 2G has the potential to significantly enhance the immune response and improve treatment outcomes.