Researchers in Barcelona have identified a previously unknown mechanism that metastatic colorectal cancer employs to evade immune checkpoint immunotherapy. A study published today in Nature Genetics reveals how these tumors use the transforming growth factor beta (TGF-β) cytokine to activate a dual barrier that blocks the immune system’s response.
“Our work shows that tumors defend themselves against immunotherapies by manipulating their environment to slow the immune response on two fronts,” said Eduard Batlle, PhD, research professor at the Catalan Institute for Research and Advanced Studies (ICREA) and head of the colorectal cancer laboratory at the Institute for Research in Biomedicine (IRB) Barcelona. “Understanding this communication language between the tumor and the immune system opens the door to designing strategies that can deactivate these defenses and thus improve the efficacy of immunotherapy.”
TGF-β has long been known to decrease the efficacy of immunotherapies, particularly checkpoint inhibitor drugs. However, clinical development of drugs targeting this molecule have faced major challenges in terms of side effects, given the important role this cytokine plays in a myriad of other cellular processes, including adhesion, proliferation, differentiation, metabolism, apoptosis and many more.
While TGF-β plays an important role as a tumor suppressor in the early stages of cancer, in later stages its overexpression can promote cancer cell growth and decrease the efficacy of immunotherapies, particularly of checkpoint inhibitor drugs. Previous studies have shown that TGF-β inhibition can enhance the effects of checkpoint inhibitors in mice, but clinical development is still underway and faces toxicity challenges due to the multiple roles this cytokine plays in a myriad of other cellular processes, including adhesion, proliferation, differentiation, metabolism, apoptosis, fibrosis and more.
Batlle and colleagues studied liver metastasis of colorectal cancer in both mouse models and human samples to shed light on how TGF-β makes the tumor resistant to immunotherapy. What they found was that TGF-β prevented immune cells from infiltrating the tumor in two steps. First, the cytokine acts directly on T cells to block their recruitment from the bloodstream. Second, it instructs tumor-associated macrophages to suppress the expansion of the few T cells that do infiltrate the tumor.
“By sequencing individual cells within the tumor microenvironment, we have been able to characterize the main players affected by TGF-β,” said Holger Heyn, PhD, research professor at ICREA and leader of the single cell genomics group at the Spanish National Centre for Genomic Analysis (CNAG). “We observed how TGF-β blocks immunotherapy efficacy and identified new therapeutic targets to improve colorectal cancer treatments.”
In particular, the researchers noted that the macrophage response triggered by TGF-β was mediated by an increase in the production of osteopontin, a protein that is known to modulate the activity of a number of immune cells including tumor-infiltrating T cells.
“In our experimental models, when we block the action of TGF-β, the immune cells were able to massively enter the tumor and regain their capacity to attack,” said Ana Henriques, PhD, postdoctoral fellow at IRB Barcelona and first author of the study. When combined with immunotherapy, this treatment resulted in very potent antitumor responses in these models.
While these effects will need to be evaluated in clinical trials, these findings support the potential of using TGF-β inhibitors in combination with immunotherapy in order to boost response rates. This could particularly benefit colorectal cancer patients with liver metastases, who are less likely to respond to immunotherapy.
“The ultimate goal for immunotherapies, which today only work in a small group of patients, is to be able to also benefit the majority of those with metastatic colorectal cancer,” said Alejandro Prados, PhD, formerly at IRB Barcelona and now a researcher at the University of Granada. “Understanding this circuit allows us to search for safer and more selective solutions.”
