Philadelphia, PA (Scicasts) - Study provides rationale for adding COX-2 inhibitors to improve anti-PD1 immunotherapy response.

In preclinical studies, tumours that consitutively expressed the protein indoleamine 2,3-dioxygenase (IDO1) responded to the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) and had improved infiltration of certain subsets of T cells, making them more likely to respond to anti-PD1 therapies.

A key challenge in cancer immunotherapy is to understand why some patients respond to immunotherapy but many others do not," said the first author Dr. Van den Eynde. "If we understand why, we can then select and treat only those patients who will benefit from the treatment, but most importantly, we can devise strategies to make immunotherapy work in those who are not currently responding."

Many tumours use IDO1 as a shield to protect themselves from immune attack, explained Van den Eynde. Some of them start building and raising their shields when they are being attacked by T cells, which is called adaptive resistance. In such tumours, IDO1 expression is associated with inflammation and T-cell infiltration.

However, some tumours produce IDO1 constitutively (continuously) and have their shields ready and raised before any immune attack. Such tumours are fully protected and can prevent T-cell attack by disabling the T cells right away.

"This is what we call intrinsic resistance and may explain why some tumours are 'cold,' meaning, not infiltrated by T cells," Van den Eynde said.

"We wanted to understand the molecular mechanisms that make some tumours express IDO1 constitutively," he added.

Using two human melanoma cell lines, Van den Eynde and colleagues first demonstrated that COX-2 and its product, prostaglandin E2 (PGE2), caused the constitutive expression of IDO1 by utilizing the MAPK, PKC, and PI3K cell-signaling pathways. These results held true in other human tumour cell lines as well, including lung, ovarian, and head and neck cancer cell lines.

"These data provide evidence that COX-2 drives tumour-induced immunosuppression through constitutive expression of IDO1," Van den Eynde noted.

Next, they showed that immunodeficient mice reconstituted with human lymphocytes and bearing human ovarian tumour xenografts with constitutive IDO1 expression responded to celecoxib as well as the IDO1 inhibitor, epacadostat.

"The outcomes we observed with COX-2 inhibitors and IDO1 inhibitors were identical, which came as a surprise," Van den Eynde said. "It is always very useful to have two compounds acting on the same pathway with two different modes of action: In case tumours start resisting one compound, they may still be sensitive to the other."

By mining the transcriptomics data of 1,041 different human tumour cell lines from the Broad Institute, the researchers found a correlation between IDO1 expression and activation of the COX-2/PGE2 axis in several cancer types, including stomach, pancreatic, liver, and lung cancers, and sarcoma.

"Our studies provide a clear rationale to test, in the clinics, combinations of anti-PD1 immunotherapy and COX-2 inhibitors," Van den Eynde said. "This should be straightforward given the fact that both anti-PD1 and COX-2 inhibitors are already approved for clinical use in different contexts."

Initial analysis by the team indicated that about 10 to 50 percent of human tumours express IDO1 constitutively, depending on tumour type.

Article adapted from a American Association for Cancer Research news release.

Publication: Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance. Hennequart, M et al. Cancer Immunology Research (July 21, 2017). Click here to view.