AURKA inhibitor-induced PD-L1 upregulation impairs antitumor immune responses

by Selleckchem | Jan 09 2024

Introduction: Tumor immunotherapy targeting PD-L1 has emerged as one of the powerful tools for tumor therapy. Numerous studies indicate that tumor-targeted drugs critically have an influence on the interaction between the immune system and tumors by changing the expression of PD-L1, which is beneficial for immunotherapy. Our study provided novel evidence for improving the drug regimen in tumor targeted therapy and immunotherapy.

Methods: The expression of PD-L1 on SKBR3, MDA-MB-231, MCF7, 4T1, MC38 and B16 cells was evaluated by flow cytometry after treatment with six preclinical targeted drugs (ARN-509, AZD3514, Galeterone, Neratinib, MLN8237 and LGK974). AURKA was knockdowned by using the specific siRNA or CRISPR-Cas9 technology. In the 4T1-breast tumor and colorectal cancer xenograft tumor models, we determined the number of infiltrated CD3+ and CD8+ T cells in tumor tissues by IHC.

Results: We found that AURKA inhibitor MLN8237 promoted the expression of PD-L1 in a time- and concentration-dependent manner while exerted its antitumor effect. Knockdown of AURKA could induce the upregulation of PD-L1 on SKBR3 cells. MLN8237-induced PD-L1 upregulation was mainly associated with the phosphorylation of STAT3. In the 4T1-breast tumor xenograft model, the infiltrated CD3+ and CD8+ T cells decreased after treatment with MLN8237. When treated with MLN8237 in combination with anti-PD-L1 antibody, the volumes of tumor were significantly reduced and accompanied by increasing the infiltration of CD3+ and CD8+ T cells in colorectal cancer xenograft tumor model.

Discussion: Our data demonstrated that MLN8237 improved the effect of immunology-related therapy on tumor cells by interacting with anti-PD-L1 antibody, which contributed to producing creative sparks for exploring the possible solutions to overcoming drug resistance to tumor targeted therapy.

Comments:

Your study is delving into a crucial area of tumor immunotherapy, focusing on the impact of targeted drugs on PD-L1 expression and the subsequent effects on immunotherapy. It's impressive how you've used various methods—flow cytometry, knockdown techniques, and xenograft models—to comprehensively explore these interactions.

The identification of MLN8237 as an AURKA inhibitor that not only affects PD-L1 expression but also demonstrates an antitumor effect is noteworthy. Understanding the mechanism behind MLN8237-induced PD-L1 upregulation via STAT3 phosphorylation adds depth to your findings.

The observed decrease in infiltrated CD3+ and CD8+ T cells in the 4T1-breast tumor xenograft model after MLN8237 treatment is intriguing. However, the subsequent reversal of this effect in the colorectal cancer xenograft tumor model when MLN8237 was combined with anti-PD-L1 antibody underscores the potential synergy between MLN8237 and immunotherapy.

Your study's implications for overcoming drug resistance in tumor targeted therapy are significant. The combination of MLN8237 and anti-PD-L1 antibody appears promising, showing reduced tumor volumes alongside increased T cell infiltration. This suggests a potential strategy for improving the efficacy of immunotherapy and combating drug resistance.

Overall, your findings contribute valuable insights into optimizing drug regimens in tumor targeted therapy, especially in the context of immunotherapy, and offer a potential avenue for further exploration in overcoming drug resistance mechanisms.