Understanding the Synergy of Cancer Growth to Advance Care

Immune checkpoint inhibitors can take the brakes off the immune system, allowing it to do its job and fight cancer.

This raises the question of whether cancer researchers can make immunotherapies that work for more patients. We asked James Gulley, MD, PhD, from the National Cancer Institute. Dr. Gulley believes we should explore approaches that can both increase the proportion of patients that respond to treatment and improve responses. Our ultimate goal is to develop approaches that may help as many patients as possible.

Recognizing the role of checkpoint inhibition pathways, such as programmed death ligand 1 (PD-L1) and programmed death cell protein 1 (PD-1), has fundamentally changed how we treat certain cancers, Dr. Gulley points out. These pathways have been shown to be very active in shutting down and preventing the immune response to fight cancer.  

When immune cells come in contact with a tumor, these cells become activated and produce proteins that initiate the immune system’s response. One of these proteins that helps generate a better immune response is called gamma interferon. However, gamma interferon can increase the amount of PD-L1 in the tumor’s microenvironment (TME). As a result, immune cells that are ready to attack the tumor are given a stop signal, ending the immune response before it can ever begin.

If the signal from gamma interferon that blocks either PD-1 or PD-L1 is interrupted, then we may break this stop signal. In turn, this may allow immune cells to do their work and try to eradicate the tumor.

Another important target Dr. Gulley notes, we have identified is transforming growth factor beta (TGF-β), a protein involved in the biology of tumors, which prevents anti-tumor responses through several processes.

TGF-β can create scarring, or fibrosis, that can decrease the ability of drugs or immune cells to reach the tumor. It can also lead to angiogenesis – or the formation of new blood vessels – that provide the tumor with essential nutrients that drive its growth. Additionally, TGF-β has negative effects on immune cells trying to kill the tumor. It can either suppress immune cell activation or it can recruit cells that dampen the immune response. Perhaps most important is epithelial-to-mesenchymal transition (EMT), a phenomenon that is driven by TGF-β. EMT causes tumor cells to spread to other parts of the body (metastasis) and also creates resistance to cancer treatments, including chemotherapy, radiation therapy and immunotherapy.

Targeting TGF-β in addition to PD-L1 may synergistically boost immune response and anti-tumor activity while targeting tumor growth and invasiveness. This is an area of on-going research.  

Explore mechanisms in the TME that may contribute to tumor growth and open new cancer targets at UncoverTheCancerBarricade.com.

*Dr. James Gulley is an investigator for multiple clinical studies with Merck KGaA, Darmstadt, Germany

References:
¹ Schmidt EV. Developing combination strategies using PD-1 checkpoint inhibitors to treat cancer. Semin Immunopathol. 2019;41:21-30.
² Tang H, Wang Y, Chlewicki LK, et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell. 2016;29(3):285-296.
³ Allard B, Aspeslagh S, Garaud S, et al. Immuno-oncology-101: overview of major concepts and translational perspectives. Semin Cancer Biol. 2018;52(pt 2):1-11.
⁴ Liu T, Han C, Wang S, et al. Cancer-associated fibroblasts: an emerging target of anti-cancer 5 immunotherapy. J Hematol Oncol. 2019;12:86. doi:10.1186/s13045-019-0770-1.
⁵ Mariathasan S, Turley SJ, Nickles D, et al. TGFß attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544-548.
⁶ Tang H, Wang Y, Chlewicki LK, et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell. 2016;29:285-296.

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