From the AGA Journals

Inhibiting adenosine pathways may be key to CRC treatment

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​​​​​​​A conceptual advance toward combinatorial therapy

Although cancer immunotherapy has emerged as a powerful treatment modality, its application to colorectal cancer (CRC) is presently restricted to the minor subclass of tumors exhibiting deficient mismatch repair and high microsatellite instability. Programmed death 1 and its ligand, PD-L1, are molecules that typically suppress tumor-killing lymphocytes, yet immune checkpoint inhibitors targeting PD-1 or PD-L1 have limited to no effectiveness in the major form of proficient mismatch repair CRC. Better definition of the immune microenvironment of the different forms of CRC could lead to new treatment regimens.

Cambrian Y. Liu, PhD Research Assistant Professor Section of Gastroenterology, Hepatology, and Nutrition Department of Medicine The University of Chicago Copyright Bogdan Condor

Dr. Cambrian Y. Liu

Recent work published by Chang Hoon Lee’s group in Cellular and Molecular Gastroenterology and Hepatology illustrates the central role of tumor-associated macrophages in suppressing the immune response to CRC. These macrophages possess biosynthetic enzymes that produce high levels of adenosine. The newly generated adenosine, in turn, alters the cellular protein processing machinery and enhances the expression of PD-L1. Importantly, as treatment of CRC with cell cycle inhibitors such as palbociclib increases expression of PD-L1 and implicates a mechanism of tumor resistance, the new work shows that combined therapy to block adenosine production (with AB680) during palbociclib treatment improves tumor outcomes in mouse models.

This study offers a conceptual advance towards combinatorial therapy that can simultaneously inhibit tumor cell proliferation and activate immune surveillance, providing clear and testable hypotheses for the clinic.

Cambrian Y. Liu, PhD, is research assistant professor in the section of gastroenterology, hepatology, and nutrition in the department of medicine, University of Chicago. He has no relevant conflicts of interest.



Research that could set the stage for future clinical trials explored the potential role of adenosine signaling in altering the immune microenvironment of colorectal cancer (CRC), according to a study appearing in Cellular and Molecular Gastroenterology and Hepatology.

The study in human-derived cells and CRC mouse models suggests that addition of a CD73 inhibitor to the CDK4/6 inhibitor palbociclib may hold promise in the treatment of CRC because CD73 can produce extracellular adenosine. The results hold promise for future research since anticancer therapies often prompt increased expression of PD-L1, and CDK4/6 inhibitor monotherapy can fail because of accumulation of PD-L1 after such treatment.

Previous research has suggested that extracellular adenosine-mediated signaling can lead to accumulation of tumor-associated macrophages (TAMs) and an immunosuppressive tumor microenvironment. TAMs play an important role in the intestinal mucosal immune system in CRC, which mediates tumor-promoting metabolites in the intestine and inflammatory pathways that can lead to and progress CRC. TAMs are also linked to increases in extracellular enzymes like CD39 and CD73 as well as resistance to chemotherapy and anti-PD-1/PD-L1 therapy in CRC. Furthermore, they express PD-L1 and they promote other immunosuppressive molecules.

In normal tissues, CD73 produces adenosine to tamp down excessive immune responses. Some tumors express CD73 or even induce expression in normal cells, leading to immunosuppression in the tumor microenvironment. Previous studies have shown that CD73 expression is a biomarker for poor outcomes in gastric, liver, pancreatic, and colorectal cancer, the authors of this study noted.

To better understand the impact of adenosine, the researchers exposed human macrophages derived from peripheral blood to adenosine, and then analyzed the results using flow cytometry and Western blot. They used RNA sequencing and proteomics to discern changes in the cells that resulted from the exposure.

Adenosine treatment led to changes in the expression levels of genes involved in the cell cycle, cell division, cell cycle phase transition, and DNA repair. The researchers emphasized that extracellular treatment with adenosine led to a reduction in expression of the cell cycle–related gene CCND1, which encodes cyclin D1. Among three genes in the cyclin D family tested, CCND1 was the only one affected by adenosine. Cyclin D1 protein levels also went down.

Cyclin D1 is a known actor in regulating the cell cycle and tumorigenesis, among other roles. Previous reports indicated that cyclin D1 participates in posttranslational regulation of PD-L1, and the current study suggests it plays a similar role in TAMs after exposure to adenosine in the tumor microenvironment. Myeloid cells high in cyclin D1 expression had low levels or even an absence of the immunosuppressive molecule CD39. “Taken together, cyclin D1 may be one of the major orchestrators that trigger the differentiation of pro-tumorigenic TAMs. Our findings suggest a novel immune checkpoint regulatory mechanism of extracellular adenosine signaling, which might be related to the cell cycle of macrophages,” the authors wrote.

The researchers then introduced a short hairpin RNA directed against CCND1. This led to increases in PD-L1 protein levels. Simultaneous treatment with adenosine led to a slight increase in levels of the PD-L1 protein, which suggests that reduction of CCND1 levels is the primary cause of increased PD-L1, according to the authors.

The CD73 inhibitor AB680, currently in phase 1 clinical trials for castration-resistant prostate cancer and advanced pancreatic cancer and developed by Arcus Biosciences, led to reduced PD-L1 levels in both human and mouse macrophages, and AB680 combined with the CDK4/6 inhibitor palbociclib led to greater inhibition of tumor growth than palbociclib alone in CRC mouse models.

“Thus, the promising effects of CD73 inhibitors might breathe new life for those old drugs and provide potent therapeutic strategies. Given that the therapeutic effects of PD-1/PD-L1 immunotherapy have not been conclusively demonstrated in patients with CRC, our observations should support clinical trials of new combinational therapies for CRC,” the authors wrote.

The authors disclose no conflicts.

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