Nat commun: immunosuppressant resistance is related to metabolic imbalance

October 21, 2019 / bioun / -- Dana Farber Cancer Institute, in collaboration with the broad Institute of MIT and Harvard University, reported that metabolic imbalance in some cancer patients after treatment with nivolumab, a checkpoint inhibitor, was related to drug resistance and shorter survival time of immunotherapy drugs The researchers said the chemical changes reflected the "adaptive resistance mechanism" of cancer cells or immune system after being treated with the anti-PD-1 antibody drug nivolumab, which was related to the reduced survival rate of patients with advanced melanoma and renal cancer The greater the change in amino acid tryptophan into a metabolite called canine urinary ammonia, the greater the impact on survival Photo source: nature communications "the main message is that metabolic adaptations in cancer immunotherapy may be related after the immune checkpoint is blocked," said Toni K choueiri, MD Metabolic process is a chemical reaction necessary to maintain life in the body, such as the process of transforming food into energy to run cells Checkpoint blockers like nivolumab are drugs that release molecular brakes on immune responses that cancer often uses to evade the attack of immune T cells One such molecular brake is called PD-1 In some patients and some cancer types, these drugs have been proved to be very effective in releasing T cells to attack tumors, but in general, these drugs can only help a small number of patients "One of the most important questions in oncology is who is responding to modern PD-1 inhibitors and who is not," said choueiri, director of the Dana Farber urogenital tumor lank center "Scientists looked at cancer tissue samples to find factors that might be more or less related to the impact of checkpoint inhibitors: including the number of cancer-related mutations found in tumor DNA, as well as other gene" signatures "related to the response to checkpoint blockers The metabolic changes that scientists have found in current research can be measured in the blood - a significant advantage of tissue-based testing "It's an attractive option to identify biomarkers of metabolic changes associated with checkpoint blocker therapy," said Dana Farber and giannakis, assistant professor of medicine at Harvard Medical School "We know that metabolism is important for immunity, and canine urinary ammonia, an elevated chemical found in most patients treated with nivolumab, is known to have immunosuppressive effects "In this study, the researchers analyzed blood samples from three independent immunotherapy trials and measured changes in metabolites (chemicals involved in metabolic reactions) at several points before and during treatment Among the patients with melanoma, 78% of the patients increased the conversion of tryptophan to canine urine ammonia in the fourth week of treatment, and 26.5% of the patients increased more than 50% in the fourth week of treatment In renal cancer patients, the treatment of nivolumab is also related to the increase of urinary ammonia Analysis showed that the higher the conversion level of tryptophan to canine urine ammonia in nivolumab, the lower the survival rate In particular, blood tests showed that the ratio of canine urine ammonia to tryptophan increased by more than 50% in melanoma The mean survival time of the patients was 15.7 months, while those with a lower survival rate had an average survival time of more than 39 months, compared with 16.7 and 31.3 months for renal cancer patients, respectively At present, researchers have not cleared up exactly how PD-1 checkpoint blockers convert tryptophan into canine urine ammonia However, an enzyme called Ido plays an important role in the synthesis of canine urinary ammonia from tryptophan, which is found in many cancers Dana Farber researchers noted that a randomized clinical trial showed no positive results in patients with advanced melanoma treated with Ido inhibitors alone However, the study did not look at the levels of urinary ammonia in these patients The researchers say their results suggest that the combination of checkpoint blockers with Ido inhibitors may "be beneficial to a specific group of patients with checkpoint inhibition triggered activation of the canine urinary ammonia pathway." Reference: Haoxin Li et al, metallic adaptations and relationships of survival to immune checkpoint blockade, nature communications (2019) Doi: 10.1038/s41467-019-12361-9