Date of Award

January 2016

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard Edelson

Abstract

Extracorporeal Photochemotherapy (ECP) is a widely used immunotherapy for cutaneous T cell lymphoma, as well as an immunomodulatory treatment for graft versus host disease (GVHD) and rejection of allografts. We hypothesized that ECP’s physiologic induction of large-scale monocyte-to-dendritic antigen presenting cell (APC) conversion is mechanistically responsible for both its anti-cancer effect and its tolerogenic impact in the transplant setting. To interrogate this possibility in an experimental system, we developed an ECP device that is scalable from mouse to man and tested its capacity to produce APCs that, when advantageously tuned and tumor antigen-loaded, can limit the growth of otherwise lethal tumors in the engineered Yale University Mouse Melanoma (YUMM) 1.7 model (driven by PTEN loss, BRAFV600E activation and CDKN2A mutations). Untreated control mouse tumors (N=169) were 7 to 10-fold (p<0.001) larger than ECP treated (N=40) tumors at the termination point, as required due to control tumor size. Depletion of ECP-induced APCs from the cellular vaccine preparation prevented the immunoprotective effect (p<0.01), indicating a primary role for ECP-induced APCs. Depletion of platelets from the ECP-processed cellular suspension also prevented the immunizing effect (p<0.01), substantiating prior in vitro evidence that physiologic ECP-induction of functional DC is signaled by transient monocyte adherence to platelets. Addition of 8-MOP-UVA-treated PBMCs to the otherwise immunoprotective APC vaccine completely reversed the immunoprotective vaccine effect (p<0.01), revealing that maturationally truncated APCs are counterproductively tolerogenic. Collectively, these results show that, in ECP, platelet-induced tumor-loaded mature APCs are immunotherapeutic for established murine melanoma, while immature APCs are tolerogenic. These findings verify a pivotal role for ECP-manufactured APCs and are the first in vivo study to suggest the intriguing possibility that ECP can be modified for immunotherapy of solid tumors.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 08/24/2017

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