CA9 as a therapeutic marker for hepatocellular carcinoma

A research group including Doctoral Student Yu Sato and Professor Takahiro Kodama of the Graduate School of Medicine at the University of Osaka, has clarified that the pre-treatment blood CA9 concentration serves as a biomarker to predict the therapeutic efficacy of atezolizumab/bevacizumab therapy, the standard first-line treatment for unresectable hepatocellular carcinoma (HCC). Furthermore, they discovered the possibility that the CA9 molecule is involved in treatment resistance. The findings were published in the Journal for ImmunoTherapy of Cancer.

Although drug treatment for unresectable HCC has advanced significantly with the advent of immune checkpoint inhibitors, there are still many cases where disease progression is observed after starting treatment, or where the expected tumor shrinkage is not achieved. Therefore, the establishment of practical biomarkers capable of predicting therapeutic efficacy and prognosis prior to the initiation of treatment has been strongly demanded.

The research group first performed high-throughput proteomic screening using Olink on the pretreatment plasma of 78 cases in a discovery cohort. As a result, they identified CA9 as a candidate molecule associated with therapeutic efficacy. Furthermore, when evaluating pre-treatment blood CA9 in an independent validation cohort of 89 cases, the high-CA9 group tended to show shorter response rates, progression-free survival, and overall survival. These results indicated that pre-treatment blood CA9 is a promising indicator for predicting the efficacy of atezolizumab/bevacizumab therapy.

Next, to clarify the origin and biological significance of blood CA9, they conducted investigations using tumor tissue analysis, public single-cell transcriptome analysis data, and mouse models. The results showed that CA9 is primarily derived from tumor cells.

Additionally, a decrease in sensitivity to anti-PD-L1/anti-VEGF antibody combination therapy was observed in a high-CA9-expressing mouse liver cancer model, indicating that CA9 is not a mere correlative molecule but may be actively involved in treatment resistance.

Furthermore, when analyzing the tumor microenvironment of high-CA9-expressing tumors, a decrease in cytotoxic T-cell infiltration, an increase in M2-like macrophages, and enhanced expression of angiogenesis-related molecules were observed. In other words, it was suggested that in high-CA9-expressing tumors, the immune response is suppressed, forming an immunosuppressive tumor microenvironment that leads to treatment resistance. Analysis of public human data also confirmed similar immunosuppressive characteristics in high-CA9-expressing tumors.

Finally, when a CA9 inhibitor was added to the anti-PD-L1/anti-VEGF antibody combination therapy, enhancement of the antitumor effect was observed in high-CA9-expressing tumors.

These results demonstrate that CA9 is a predictive biomarker for therapeutic efficacy in unresectable HCC and, at the same time, can serve as a new therapeutic target aimed at overcoming treatment resistance.

Kodama stated: "Although drug therapy for liver cancer patients has advanced significantly in recent years, limitations in therapeutic efficacy still remain, and problems with side effects are not uncommon. Our Department of Gastroenterology and Hepatology works daily on research and medical care with the mission of 'delivering the optimal treatment to the optimal patient.' We hope that the results of this study will advance the personalization of liver cancer treatment by one step and bring hope to as many patients as possible."

Journal Information
Publication: Journal for ImmunoTherapy of Cancer
Title: Carbonic anhydrase 9 as a circulating biomarker and therapeutic target in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab
DOI: 10.1136/jitc-2025-013384