Date of Graduation
5-2015
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Padmanee Sharma, M.D Ph.D.
Committee Member
Gary Gallick, Ph.D.
Committee Member
Michael Davies, M.D. Ph.D.
Committee Member
Nizar Tannir, M.D.
Committee Member
Arlene Siefker-Radtke, M.D.
Abstract
THERMAL ABLATION ALTERS THE TUMOR MICROENVIRONMENT ACTIVATING A ROBUST IMMUNE RESPONSE.
Matthew T Campbell, M.D.
Advisor Professor: Padmanee Sharma, M.D Ph.D
Ablation techniques including radiofrequency ablation (RFA) and cryoablation have been shown to influence the immune system in animal models. Rare abscopal events, a distant metastatic response to a local procedure, have been observed in humans following both RFA and cryoablation. These rare observations have led to interest in further defining the impact of ablation procedures on the immune signature in the tumor microenvironment and in the systemic circulation.
Retrospectively 9 patients with nephrectomy alone (control) were compared to 16 patients treated with ablation. Gene microarray analysis and immunohistochemistry (IHC) for presence of immune cell subtypes were performed on the tissue samples. Prospectively, blood was collected from patients 13 patients who underwent renal ablation for renal cell carcinoma for stage T1a (less than 4cm) at baseline and at day 1, day 28, and 6 months following the procedure. The blood was assessed by flow cytommetry and plasma cytokine levels at each time point following the procedure. GraphPad Prism version 6 was used to perform statistical analysis. The student’s t-test, Kruskal Wallis test, Friedman’s test, and Dunn’s multiple comparisons test were used when appropriate.
IHC identified a significant difference (p=0.04) in programmed cell death 1 (PD-1) levels in the tumor invasive margin when comparing control to ablated tumors, while other tumor stains showed no significant differences between the two groups. Gene microarray analysis comparing control patients to three ablation specimens after RFA found significant differential gene expression in pathways and processes involving the immune system. Flow cytommetry markers consistent with previously characterized T regulatory populations of immune cell were found to trend upward at 24 hours following ablation compared to baseline levels. Cytokine analysis revealed elevated levels of IL-6 that increased at day 1 and returned toward baseline by day 28.
RFA and cryoablation cause local tissue destruction and an inflammatory immune response that can be detected by gene microarray. Significant changes in tissue IHC, plasma cytokine levels, and immune cell populations in peripheral blood flow cytommetry analysis were not detected.
Keywords
Thermal ablation, renal cell carcinoma, immune response, radiofrequency ablation, cryoablation, immune gene signature