Disabling autophagy can enhance immune response in melanoma

Researchers discover that disabling autophagy in Tumor Endothelial Cells, inflames them and leads to a better immune response

28 November 2023 – Researchers at the VIB-KU Leuven Center for Cancer Biology have gained unprecedented insights into the immunosuppressive role of autophagy in tumor endothelial cells (TEC). The team, led by Professor Patrizia Agostinis, found that inhibiting autophagy in the endothelial cells lining tumor blood vessels can inflame them and evoke an antitumor immune response. This could provide an additional strategy to help sensitize patients to immunotherapy. The results of this research were published in the prestigious scientific journal EMBO Molecular Medicine

One of the bigger challenges in immunotherapy is that tumors build a network of abnormal blood vessels able to impair the ability of our immune system to infiltrate the tumor and kill cancer cells. Tumor blood vessels can suppress the functioning of immune cells in several ways including blocking the recruitment and the activity of T lymphocytes, the soldiers of our immune system fighting the tumor. Drugs or strategies that could reverse this potent barrier ability of tumor blood vessels have the potential to improve immunotherapy and are therefore a valid target in cancer research.

While researchers have long struggled to fully understand the exact mechanisms responsible for this, research by Professor Patrizia Agostinis’s team at the VIB-KU Leuven Center for Cancer Biology, provides novel insights into the mechanisms that support the immunosuppressive nature of tumor blood vessels. In a research paper published in EMBO Molecular Medicine, the team demonstrates that halting autophagy, specifically in endothelial cells could increase the responsiveness of patients to immunotherapy.

FLTR: Jelle Verhoeven, Patrizia Agostinis and Kathryn Jacobs, VIB-KU Leuven Center for Cancer Biology
FLTR: Jelle Verhoeven, Patrizia Agostinis and Kathryn Jacobs, VIB-KU Leuven Center for Cancer Biology

Cleaning up the cleaning crew

Cells can be considered as tiny machines made up of several essential components. Much like with any machine, wear and tear can cause components of a cell to malfunction. When that happens, a natural response is to either repair the component or remove it and clean up the mess. Similarly, our cells keep things tidy through a cellular process called autophagy. By acting as a self-cleaning mechanism, autophagy breaks down and recycles damaged or dysfunctional components within our cells. While this is generally an essential process to keep cells healthy it also benefits more malicious cell types such as those found in tumors.

To investigate this, the team of Professor Agostinis examined whether halting autophagy in TECs could enhance the effectiveness of the immune system. In mouse models of melanoma Dr. Jelle Verhoeven and Dr. Kathryn Jacobs, the first authors of the study, showed that deleting genes that are necessary for autophagy to function in endothelial cells, leads to more inflamed tumor vessels. Blocking the capability to recycle through autophagy, turned on a beneficial inflamed response in these tumor vessels. As a result of this, more and more active T cells could infiltrate into the tumor which ultimately limited tumor growth and favored immunotherapy.

Patrizia Agostinis, VIB-KU Leuven Center for Cancer Biology: “Cancer has a way of turning our own body against ourselves. Fundamental biological processes such as autophagy can unintentionally contribute to the survival of a tumor and reduce the ability of our immune system to recognize it and eliminate it. Whereas it fulfills an essential role in regular housekeeping activities in the body, in the context of cancer, it does its job too well, preventing our immune system from recognizing cancer cells as irregular. Most studies so far have only focused on autophagy in cancer cells. What we discovered goes beyond cancer cells and shows that autophagy keeps tumor vessels in an immunosuppressive status, preventing our immune system from doing its job. While chronic inflammation in cancer is generally a bad thing, inflammatory responses also help our immune system to kill the tumor. Our findings show that if we can halt the ability of autophagy to suppress inflammation, tumor vessels promote immune responses and increase the efficacy of immunotherapy.”
Kathryn Jacobs, VIB-KU Leuven Center for Cancer Biology adds: The word autophagy is trendy these days, we hear about it more and more as people try to induce it via intermittent fasting. Most think inducing autophagy can only be a good thing. While autophagy can be beneficial in cleaning up our healthy cells and preventing cancer when cancer is there, it does just the opposite; it helps cancer hide by toning down our immune responses and allowing cancer cells to survive.”

Looking ahead

These new insights underline the importance of designing vascular-homed autophagy inhibitor drugs to be used in combination with immune checkpoint blockers (ICB), a type of immunotherapy.

Jelle Verhoeven, VIB-KU Leuven Center for Cancer Biology: “Our findings are merely the beginning. While immunotherapy has shown great promise in many cancer types already, one of the main hurdles that still needs to be overcome is that not all patients respond to it. By combining immunotherapy with complementary strategies that help break down the defenses of tumors against our own immune system, we can potentially enhance its effects.”

The results of this study could, in time, lead to improved immunotherapy options in specific cancer types. However, more research will be needed to further explore the applications of this research.


Publication

Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma. Verhoeven et al. EMBO, 2023. DOI: 10.15252/emmm.202318028


Joran Lauwers

Joran Lauwers

Science & Business Communications Expert, VIB

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