The immune system has emerged as a pivotal target for innovative cancer treatments, particularly in the realm of immunotherapy. Among the most promising approaches are immune checkpoint inhibitors and CAR-T cell therapy, which have the potential to significantly enhance treatment outcomes for various forms of cancer. However, a staggering 70% of patients do not experience the desired effects from these advanced therapies.
Researchers at the University of Michigan Rogel Cancer Center have identified a crucial factor that explains the lack of response to immunotherapy in certain cancers: the presence of a metabolite transporter located within the tumor microenvironment. This transporter blocks a vital mechanism of tumor cell death that is integral to the immune response.
Tumor cells have evolved their metabolic pathways to effectively evade immune-based therapies. Gaining insights into these mechanisms of immune resistance could pave the way for new therapeutic targets, ultimately refining immune-based treatments to benefit a larger cohort of patients. Our discovery marks a meaningful advancement toward that objective.”
Weiping Zou, M.D., Ph.D., senior study author, director of the Center of Excellence for Cancer Immunology and Immunotherapy at the Rogel Cancer Center
In this groundbreaking study, published in Cancer Cell, the researchers observed that elevated levels of SLC13A3 in tumor samples from patients correlated with a poor response to immunotherapy and diminished overall survival rates. They conducted tests using tumor samples obtained from diverse cancer types across multiple medical institutions.
The findings were further validated using tumor-bearing mouse models where researchers selectively knocked out SLC13A3. This genetic modification resulted in a notable reduction in tumor development and progression. In contrast, restoring SLC13A3 levels stimulated tumor growth. Notably, they also observed an increased presence of immune cells in mice from which SLC13A3 was deleted, as opposed to those retaining SLC13A3 expression.
Taking their research a step further, investigators uncovered the underlying mechanism: tumor cells exploit SLC13A3 to absorb a metabolite known as itaconate. This metabolite subsequently triggers a ferroptosis-resistant mechanism, rendering the tumor cells able to withstand ferroptotic cell death and thus unresponsive to immunotherapy.
Itaconate is produced by macrophages within the tumor microenvironment, leading to a detrimental interaction between macrophages and tumor cells mediated by SLC13A3.
In a collaborative effort with Shaomeng Wang, M.D., Ph.D., and his team, researchers successfully constructed a structural model of SLC13A3 to screen for and identify a promising inhibitor, designated SLC13A3i. This inhibitor has the potential to obstruct the uptake of itaconate by tumor cells, reversing their resistance to ferroptosis. Efficacy tests involving this inhibitor were performed on mice, both as a standalone treatment and in conjunction with an immune checkpoint inhibitor. The SLC13A3 inhibitor alone effectively reversed ferroptosis resistance, leading to tumor remission in the mice. When used in combination, the two inhibitors markedly inhibited tumor progression while enhancing the effectiveness of the immune-based therapy.
“Our findings underscore the pivotal role of SLC13A3 in determining the fate of tumor cells and the efficacy of immune-based cancer therapies. SLC13A3 represents a promising target for the development of clinically applicable inhibitors that could significantly improve the effectiveness of immune-based treatments for a greater number of patients,” Zou stated.
Additional authors: Heng Lin, Kole Tison, Yuheng Du, Paul Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas Vigil, Yatrik M. Shah, Richard Mortensen, Ilona Kryczek, Lana Garmire, Jwala P. Sivaccumar, Ashwin Kumar Ramesh, Ningyan Zhang, Zhiqiang An.
Funding for this research was generously provided by grants from the National Cancer Institute: CA248430, CA217648, CA123088, CA099985, CA193136, CA152470, R01CA148828, and P30CA46592, in addition to funding from the Welch Foundation.
Source:
Michigan Medicine – University of Michigan
Journal reference:
Lin, H., et al. (2024). Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance. Cancer Cell. doi.org/10.1016/j.ccell.2024.10.010.
Weiping Zou Lab
**Interviewer:** Thank you for joining us today, Dr. Weiping Zou, to discuss your groundbreaking research on the SLC13A3 metabolite transporter and its role in cancer immunotherapy resistance. Your findings certainly represent an important step forward. Could you start by explaining what SLC13A3 is and why it’s significant in the context of tumor immunity?
**Dr. Zou:** Thank you for having me. SLC13A3 is a solute carrier transporter that specifically facilitates the uptake of certain metabolites, including itaconate, within tumor cells. Our research shows that high levels of this transporter correlate with a poor response to immunotherapy and lower overall survival rates in cancer patients. Essentially, SLC13A3 plays a key role in determining how well tumor cells can evade the immune response.
**Interviewer:** Fascinating! You mentioned that SLC13A3 seems to contribute to the survival of tumor cells by interfering with the ferroptotic cell death pathway. Can you elaborate on that mechanism?
**Dr. Zou:** Certainly. Tumor cells have adapted their metabolic pathways to resist treatments. They use SLC13A3 to absorb itaconate, a metabolite produced by macrophages in the tumor microenvironment. This absorption triggers a resistance mechanism to ferroptosis, which is a type of regulated cell death. As a result, the tumor cells become more resilient and less responsive to immunotherapeutic interventions.
**Interviewer:** You also conducted experiments with tumor-bearing mouse models. Can you discuss what you found regarding the genetic knockout of SLC13A3?
**Dr. Zou:** Yes, indeed. By selectively knocking out the SLC13A3 transporter in mouse models, we observed a significant reduction in tumor development and progression. Moreover, the deletion of SLC13A3 led to an increased presence of immune cells in the tumors, indicating that the immune system was more active and effective in targeting the tumors in the absence of this transporter.
**Interviewer:** That’s quite promising! The discovery of the SLC13A3 inhibitor you mentioned is particularly exciting. How does this inhibitor work, and what potential does it have for future cancer treatments?
**Dr. Zou:** The inhibitor, which we’ve designated SLC13A3i, is designed to prevent tumor cells from absorbing itaconate. By blocking that pathway, we could reverse the resistance mechanism to ferroptosis and enhance the effectiveness of immunotherapies. Our preliminary tests in mice suggest that this strategy could improve treatment outcomes, and we hope it paves the way for clinical trials.
**Interviewer:** It sounds like your team is making significant strides towards refining immune-based cancer treatments. What do you see as the next steps in this research?
**Dr. Zou:** Our next steps involve further validating the efficacy of SLC13A3i in preclinical models, followed by potential clinical trial preparations. We also hope to explore whether measuring SLC13A3 levels could serve as a biomarker to predict responses to immunotherapy in patients. Ultimately, our aim is to make these promising treatments accessible to a broader range of patients.
**Interviewer:** Thank you, Dr. Zou, for sharing your insights. It’s clear that your research could have a substantial impact on improving immunotherapy outcomes for cancer patients. We look forward to hearing more about your findings in the future!
**Dr. Zou:** Thank you for having me. I appreciate the opportunity to discuss our work!
