Release of Danger-Associated Molecular Patterns following Chemotherapy Does Not Induce Immunoparalysis in Leukemia Patients

Abstract

Chemotherapy may result in the release of danger-associated molecular patterns (DAMPs), which can cause immunoparalysis (deactivation of the immune system). We investigated DAMPs following chemotherapy and their relationship with markers of immunoparalysis in leukemia patients. In 6 patients with acute myeloid leukemia or myelodysplastic syndrome and 12 healthy subjects, DAMPs, cytokines, and markers of immunoparalysis were determined before and during the first week after chemotherapy initiation. In the patients, plasma levels of nuclear DNA (a marker of general DAMP release) were profoundly increased before chemotherapy and further increased 4-6 h afterwards, while the specific DAMP mitochondrial DNA showed only a trend towards increase. Circulating cytokine levels did not change following chemotherapy. Leukocyte cytokine production capacity and HLA-DR expression were similar in patients and healthy controls until day 4 when leukocytes were found to be virtually absent. In conclusion, in the early phase following chemotherapy in leukemia patients, increased DAMP release does not induce immunoparalysis.

Increased Plasma Levels of Danger-Associated Molecular Patterns Are Associated With Immune Suppression and Postoperative Infections in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

“…Our data show that the CRS-HIPEC procedure results in the release of DAMPs and LDH, suggesting noticeable cellular damage, (unscheduled) cell death, and/or cellular stress. This observation is in accordance with previous studies of our group in cohorts of trauma, sepsis, cardiac arrest, and chemotherapy-treated leukemia patients ( 13 , 19 , 30 , 31 ). It is well known that virtually all DAMPs are released as a result of cellular rupture and/or decay ( 23 , 32 , 33 ).…”

“…Nevertheless, it is conceivable that chemotherapy-mediated apoptosis could contribute to prolonged DAMP release in these patients. Interestingly, similar to what was observed in trauma and chemotherapy-treated patients ( 13 , 19 ), but unlike findings in patients with septic shock or cardiac arrest ( 30 , 31 ), mtDNA levels did not significantly increase in our patient cohort, and no correlations with other DAMPs were present. This suggests that other release or clearance mechanisms exist for this DAMP, as has been proposed before ( 30 ).…”

“…Like trauma, major surgical procedures and chemotherapy are thought to cause profound cellular stress and consequent DAMP release ( 18 , 19 ). This led us to hypothesize that the CRS-HIPEC procedure, comprising a double hit of surgical trauma and hyperthermic chemotherapy, causes excessive DAMP release, which in turn contributes to a systemic inflammatory response and the development of immune suppression ( 20 ).…”