Cancer discoveries could enhance immunotherapy, breast cancer care

The Dudley lab at UVA Cancer Center has unveiled two groundbreaking findings that shed light on the distinct functions of blood vessels within solid tumors. These discoveries have the potential to significantly impede the spread of breast cancer and amplify the efficacy of a revolutionary cancer treatment, considered one of the most crucial advancements in recent times.

In a recent scientific publication, Dr. Andrew C. Dudley and his research team from the Dudley lab at UVA Cancer Center have revealed that the efficacy of immune checkpoint blockade, a type of immunotherapy that boosts the immune system’s ability to combat cancer and other illnesses, can be significantly improved by targeting blood vessels in a specific manner.

Additionally, in another forthcoming paper, Dr. Dudley and his collaborators have outlined a significant breakthrough that offers potential in preventing the metastasis, or spread, of breast cancer to different regions of the body. This discovery holds tremendous promise for advancing our understanding of breast cancer and potentially developing strategies to halt its metastatic progression.

Blood vessels can have two different effects on a growing tumor. They can be helpful by allowing immune cells to enter the tumor and destroy cancer cells. However, they can also be harmful by providing a pathway for cancer cells to enter the bloodstream and spread to other parts of the body. This research emphasizes the importance of understanding the dual role of blood vessels in cancer, as it can help us find better ways to activate the immune system against tumors or stop cancer from spreading to other areas.

Improving Cancer Immunotherapy

In their immunotherapy study, Dudley and his team explain how they propose targeting the blood vessels that supply nutrients to a tumor, known as tumor vasculature. Their aim is to facilitate the entry of immune cells into the tumor and enhance their ability to eliminate cancer cells.

The researchers discovered that an enzyme called DNMT1 plays a crucial role in controlling the access of anti-tumor immune cells into the tumor’s “microenvironment” through blood vessels. By disabling this enzyme specifically in the blood vessels, they observed a reduction in vessel growth and an increased ability for immune cells to enter the tumor. This improvement in immune cell entry resulted in a better response to immunotherapies.

Doctors could potentially enhance the infiltration of anti-tumor immune cells into patients’ tumors and enhance the destruction of cancer cells by using drugs to block this enzyme. This strategy could be utilized alongside current immunotherapy methods to increase the proportion of patients who positively respond to treatment, as suggested by the researchers.

Dudley explained that while blocking DNMT1 activity in cancer cells has already been demonstrated to improve the effectiveness of cancer immunotherapies, their research revealed that DNMT1 is also a viable target in the blood vessels associated with cancer. It appears that inhibiting DNMT1 in the blood vessels is equally significant in the context of cancer treatment.

PREVENTING METASTASIS

In another research paper, Dudley and his collaborators provided valuable insights into the process of how breast cancer cells spread from the primary tumor to other areas of the body, including the lymph nodes. Understanding this mechanism is crucial, as patients whose cancer spreads to the lymph nodes generally have poorer prognoses, especially in the case of breast cancer. The findings contribute to our understanding of the disease and may have implications for improving treatment outcomes.

Dudley and his team discovered that highly metastatic breast cancer cells have the ability to stimulate the activity of fibroblast cells, which then modify the surrounding environment. This modification facilitates the escape of cancer cells from the tumor, allowing them to enter the lymphatic vessels and spread to the lymph nodes. The researchers suggest that by using drugs to disrupt this process at an early stage, it may be possible to prevent the spread of breast cancer. This highlights a potential strategy for preventing the metastasis of breast cancer cells.

Dudley stated that this study has provided important insights into how cancer cells can manipulate non-cancerous cells in their vicinity, altering their behavior to facilitate the process of entering blood vessels and spreading to other parts of the body, particularly the lymph nodes. He emphasized that cancer is a cunning disease, and this example highlights the challenges in treating it. He suggests that therapies targeting both cancer cells and the non-cancerous cells that support tumor growth may be advantageous in the future.

Dudley hopes his lab’s new findings will help advance the battle against cancer, a key mission of UVA Cancer Center, which has been designated one of only 54 Comprehensive Cancer Centers in the country by the National Cancer Institute. The NCI’s Comprehensive Cancer Center designation recognizes elite cancer centers with the most exceptional cancer programs in the nation. Comprehensive Cancer Centers must meet rigorous standards for innovative research and leading-edge clinical trials, positioning them at the leading edge of cancer care.

Dudley expressed that cancer is not isolated but exists within a complex ecosystem or microenvironment where it flourishes. By gaining a deeper understanding of how cancer cells exploit this microenvironment, it is possible to explore new therapeutic approaches, enhance the effectiveness of existing drugs, and potentially even prevent the spread of cancer. The aim is to leverage this knowledge to develop strategies that disrupt the favorable conditions for cancer growth and metastasis.

Findings Published

Dudley and his collaborators have published their immune checkpoint blockade findings in the scientific journal Nature Communications. The team consisted of Dae Joong Kim, Swetha Anandh, Jamie L. Null, Piotr Przanowski, Sanchita Bhatnagar, Pankaj Kumar, Sarah E. Shelton, Erin E. Grundy, Katherine B. Chiappinelli, Roger D. Kamm, David A. Barbie and Dudley. Dudley reported no financial interest in the work; a full list of the other authors’ disclosures is included in the paper.

The metastasis findings have been published in the journal Cancer Research. That team consisted of Null, Kim, James V. McCann, Patcharin Pramoonjago, Jay W. Fox, Kumar, Lincy Edatt, Chad V. Pecot and Dudley. The researchers reported no financial interests in the work.

The metastasis work was supported by the National Cancer Institute, awards F31CA247407-02, T32CA009109, 2R01 CA177875, R01 CA2558451 and 5P30CA044579; the American Cancer Society, award 129755-RSG-16-176-DDC; the Melanoma Research Alliance, award ID612638; and UVA’s Emily Couric Cancer Center and the UVA Genome Analysis and Technology Core.

The immune checkpoint blockade research was supported by the National Cancer Institute, awards 2R01 CA177875, R01 CA2558451, R01 CA248930, U01CA214381 and U54CA261694; a National Institutes of Health postdoctoral fellowship, K00CA212227; the American Cancer Society, award 129755-RSG-16-176-DDC; the Melanoma Research Alliance, award ID612638; and UVA’s Emily Couric Cancer Center.

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