Chemotherapy Necessitates Increased Immune Control of HHVs: A Cause of Persistent Inflammation Enabling Protracted Fatigue in Breast Cancer Survivors
Final summary rept. 15 Sep 2011-30 Apr 2015
MEDICAL UNIV OF SOUTH CAROLINA CHARLESTON
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We hypothesized that chemotherapy would induce a shift in control of chronic human herpes viruses HHVs in breast cancer patients and that this alteration may drive protracted cancer treatment related fatigue CTRF on account of enhanced inflammatory cytokine production. We examined three cohorts of patients in order to test our hypothesis. Cohort 1 consisted of breast cancer patients actively undergoing chemotherapy n14. Cohort 2 was comprised of breast cancer patients who had previously undergone chemotherapy and continued to present with active disease n20. Cohort 3 consisted of breast cancer survivors, previously treated with chemotherapy, who were disease free for at least two years n97. We found that EBVCMV double positive status was predictive of significantly elevated levels of sera INF- in Cohort 1 and Cohort 2. Analysis of CD8 T cells from PBMC showed that immuno-dominant CMV epitope IE1 drove elevated IFN- levels in breast cancer patients who were undergoing chemotherapy compared to all other viral epitopes tested. IFN-gamma derived from IE1-specific CD8 T cells was predictive of serum CRP levels, albeit a negative correlation. In subjects with active disease and previously treated with chemotherapy, EBVCMV status predicted a significant and positive association between serum IFN-gamma and serum CRP levels. Finally, among breast cancer survivors, EBVCMV patients showed a significant and positive correlation between CTRF score and serum CRP, and this relationship did not exist in EBV alone subjects. Taken together our data suggest that, in association with chemotherapy, CMV drives an enhanced inflammatory milieu in breast cancer patients and survivors marked early by IFN-gamma produced by IE1 specific CD8T cells and marked later by elevated levels of CRP. Further, the aforementioned parameters may be strongly predictive of protracted CTRF in breast cancer patients and survivors.
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