Enhancing Anti-Tumoral Immunity by Inhibiting Specific Enzyme

Enhancing Anti-Tumoral Immunity by Inhibiting Specific Enzyme

In a new study entitled “Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy” researchers showed that inhibiting an enzyme – dipeptidylpeptidase 4 (DPP4) – responsible for the degradation of key immune signals, increases the number of immune cells within the tumor microenvironment, leading to an efficient anti-tumoral response. The study was published in the journal Nature Immunology and is already being translated into a phase I clinical trial.

Immune responses against tumors depend on a specialized type of immune cells – T cells – to target and infiltrate the tumor microenvironment, consequently destroying cancer cells. Chemokines are a family of small signaling proteins secreted by cells that guide T cells towards tumors. However, these molecules can be degraded by enzymes, halting T cell infiltration and consequently tumor destruction by the immune system. One of these enzymes, dipeptidylpeptidase 4 (DPP4), degrades the chemokine CXCL10 responsible for targeting T cells into diseased tissues.

In this study, researches at the Institute Pasteur led by Matthew Albert, showed that inhibiting the activity of DPP4 improves the immune efficacy, particularly against tumors. The team confirmed that DPP4 activity in vivo limited immune cells’ migration towards tumors and other inflammatory locations within the body. Upon inhibition of DPP4 activity in mice, using a specific DPP4 inhibitor – sitagliptin, researchers observed that blocking this enzyme preserved the biological activity of the CXCL10 chemokine, resulting in an increase of the respective T cells into the tumor environment, therefore inhibiting tumor growth. Furthermore, the team showed DPP4 inhibition combined with other forms of immunotherapy (adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade) led to an increased efficiency of the overall immune response.

DPP4 inhibitors have already been approved as a treatment for type 2 diabetes, thus allowing a faster translation of these results into clinical trials with cancer patients. Currently, the team is collaborating with clinicians to perform phase I clinical trials on hepatocellular carcinoma patients and determine their response to treatment with sitagliptin.

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