Project Grant R21CA287678

IL-6 AND IL-6R GENETIC POLYMORPHISMS IN IMMUNE-RELATED ADVERSE EVENTS CAUSED BY CANCER IMMUNOTHERAPY - SUMMARY THE ACHIEVEMENTS OBTAINED WITH DIFFERENT TYPES OF CANCER IMMUNOTHERAPY ARE CLEAR, WITH DURABLE LONG-TERM SURVIVAL IN SOME CASES. THE MOST FREQUENTLY USED IMMUNOTHERAPEUTIC APPROACH IS THE TREATMENT WITH IMMUNOCHECKPOINT INHIBITORS (ICI). HOWEVER, THE MAJOR LIMITATION OF THESE IMMUNOTHERAPIES IS THE RELATIVE HIGH FREQUENCY OF LONG-LASTING IMMUNO-RELATED ADVERSE EVENTS (IRAES) ASSOCIATED WITH THE TREATMENTS. IRAES TRIGGERED BY ICI CAN AFFECT MOST ANY TISSUE. THUS, GIVEN THE INCREASING BURDEN OF IRAES, DETERMINING A) THE MECHANISMS THAT DRIVE THE IRAES, B) THOSE PATIENTS WHO ARE AT A HIGHER RISK TO DEVELOP IRAES, AND C) NOVEL STRATEGIES TO MINIMIZE IRAES WHILE SUSTAINING THE ICI ANTI-TUMOR EFFICACY ARE UNMET NEEDS. THE IRAES CAUSED WITH ICI TREATMENTS ARE MAINLY DUE TO AN OVERRESPONSE OF CD4 AND CD8 CELLS, AND T CELL-PRODUCED CYTOKINES ARE A MAJOR MEDIATOR OF IRAES. UNTIL RECENTLY, MINIMAL ATTENTION WAS GIVEN TO IL-6 AS A MEDIATOR OF THE IRAES FROM ICI THERAPY, DESPITE THE WELL-ESTABLISHED ROLE OF IL-6 IN THE PATHOGENESIS OF A NUMBER OF INFLAMMATORY DISEASES. THIS IS IN PART DUE TO THE FACT THAT IL-6 IS CONSIDERED A CYTOKINE PRODUCED BY THE INNATE IMMUNE SYSTEM. WE HAVE RECENTLY SHOWN THAT HUMAN CD4 CELLS (BUT NOT MOUSE CD4 CELLS) FROM HEALTHY VOLUNTEERS PRODUCE HIGH LEVELS OF IL-6 QUICKLY AFTER ACTIVATION. THE LEVELS OF IL-6 PRODUCED BY HUMAN CD4 CELLS AFTER ACTIVATION ARE HETEROGENOUS AMONG HEALTHY VOLUNTEERS, SUGGESTING A POTENTIAL GENETIC INFLUENCE. ALTHOUGH IL-6R EXPRESSION IS RESTRICTED TO LEUKOCYTES AND HEPATOCYTES, IL-6 CAN ALSO TRIGGER SIGNALS IN CELLS THAT DO NOT EXPRESS IL-6R (E.G. ENDOTHELIAL CELLS, NEURONS, CARDIOMYOCYTES) AND CAUSE PATHOLOGY WHEN SOLUBLE IL-6R (SIL-6R) IS PRESENT, BINDS TO IL-6 AND ASSOCIATES WITH UBIQUITOUSLY EXPRESSED GP130. WE HAVE SHOWN THAT HUMAN CD4 CELLS PRODUCE HIGH LEVELS OF SIL- 6R UPON ACTIVATION. THERE IS A HIGH-FREQUENCY POLYMORPHISM IN THE PROMOTER OF HUMAN IL-6 GENE (-174G/C, RS1800795) THAT CAN AFFECT THE PRODUCTION OF IL-6. SIMILARLY, A POLYMORPHISM (RS2228145) IN THE CODING REGION OF THE IL-6R GENE CAN LEAD TO ENHANCED LEVELS OF SIL-6R. WE PROPOSE THAT THE IL-6 AND/OR SIL-6R PRODUCED BY ACTIVATED CD4 CELLS AFTER TREATMENT OF CANCER PATIENTS WITH ICI ARE MAJOR MEDIATORS OF THE IRAE CAUSED BY THIS THERAPY, AND THAT THE GENETIC POLYMORPHISMS IN IL-6 AND/OR IL-6R GENES COULD DETERMINE THE RISK OF PATIENTS TO DEVELOP IRAE. WE WILL INVESTIGATE: 1) THE EFFECT OF GENETIC POLYMORPHISMS ON THE PRODUCTION OF IL-6 AND SIL-6R BY HUMAN CD4 CELLS FROM HEALTHY VOLUNTEERS; 2) WHETHER POLYMORPHISMS IN IL-6 AND/OR IL-6R GENES ARE ASSOCIATED WITH THE DEVELOPMENT OF IRAE IN ICI-TREATED CANCER PATIENTS.