Novel target for colorectal cancer immunotherapy discovered
Researchers from the Medical University of South Carolina (SC, USA) have identified novel targets for the immune directed treatment of colorectal cancer, where previous immunotherapies have proved unsuccessful.
Immune directed cancer therapy
In a normal immune system, PD-1 proteins present on activated T-cells recognize PD-L1 ligands on ‘self’ cells. The binding of these two entities essentially acts as a ‘checkpoint’ to prevent the immune system from attacking itself. However, cancer cells have been known to exploit this system by presenting PD-L1 themselves – enabling them to evade immune attack.
Immunotherapies are therefore an emerging method for the treatment of cancer. Notably, checkpoint therapies such as PD-1 inhibitors have been successful against many forms of cancer including melanoma, non-small cell lung cancer and kidney cancer.
Despite the promise of this treatment, PD-1 inhibitors have shown disappointing results when used to combat colorectal cancer.
GARP is a novel potential target
Zihai Li, chair of the Department of Microbiology and Immunology at the Medical University of South Carolina (MSCU; SC, USA) and co-leader of the cancer immunology research program at MUSC Hollings Cancer Center, and fellow researchers have recently published a paper in Cancer Research, detailing the identification of a novel target for the immune directed therapy of colorectal cancer – GARP.
"In terms of cancer therapy, the immune system has so many buttons you can push," commented Li. "PD-1 checkpoint therapy is an example of that. Researchers are constantly looking for more buttons to push, and I think that GARP could be one of those buttons."
GARP is a protein that is expressed by regulatory T (Treg) cells, which function to regulate and suppress other cells in the immune system, thus establishing ‘tolerance’. Li and his group found that disrupting GARP reduced the tolerance of the immune system, thus allowing the immune system to attack the cancer.
"Fundamentally we shed some light on basic Treg cell biology," explained Li. "We found that GARP, specifically that on Treg cells, is important for immune tolerance. It also seems to be involved in immune evasion by cancers in the gut."
In the study, GARP was genetically deleted from Treg cells in a mouse model of colitis, leading to the insufficient suppression of the immune system. This resulted in the depletion of tumors by 50% when compared to mice with intact GARP.
"In our preclinical cancer model, mice with no GARP on their Treg cells had a better outcome, and more T cells infiltrated the tumor," commented Li. "Interestingly, this only seems to be the case in the gut. When we induced cancer in other places like the skin, there was no difference between mice with or without GARP on Treg cells."
GARP and TGF-β: bringing it home
As well as GARP, TGF-β has been found to play a key role in the regulation of Treg cells — and assists their migration into the gut during colon cancer.
Li and his team found that CD103, a cell surface protein, is the ‘homing signal’ which induces Tregs’ influx into the gut. They hypothesized that inhibiting CD103 could reduce the activity of Treg in the colon – thus reducing the expression of colorectal cancer.
"When GARP is expressed on the surface of Treg cells, it can grab TGF-β that's secreted from other cells," explains Li. "This causes an upregulation in CD103 expression, which acts like a zip code to the gut for Treg cells."
This research has ultimately uncovered the roles of GARP and TGF-β in Treg cell regulation – and has highlighted more possible options for future immune directed therapies for cancer.
Sources: Salem M, Wallace C, Velegraki M. GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon. Cancer Res. 79(6) 1178-1190 (2019); https://www.eurekalert.org/pub_releases/2019-03/muos-hso031819.php