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The function of tumor associated leukocytes in ovarian cancer growth.

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Call No.	QP95 .B35 2009
Author	Bak, S. Peter G.
Title	The function of tumor associated leukocytes in ovarian cancer growth.
Date	2009
Abstract	Immunosuppressive leukocytes are emerging as a critical factor in facilitating tumor progression. These leukocytes are converted by the tumor microenvironment to become tolerogenic, facilitate metastasis, and to aid in neo-vascularization. The predominant variety of suppressive leukocytes found in ovarian cancer are referred to as vascular leukocytes (VLCs), due to cell surface markers of both dendritic cells and endothelial cells. Despite the large infiltration of VLCs in ovarian ascites, their derivation, mechanisms by which they facilitate tumor progression, and effect on the global immune system are not well understood. Using the ID8 tumor cell line, and focusing on peritoneal tumor growth, we further define the phenotype and function of VLCs. We show that carrageenan-mediated depletion of peritoneal tumor-associated leukocytes inhibits ovarian tumor progression. Moreover, Scavenger Receptor-A (SR-A) is robustly and specifically expressed on VLCs within human and murine ovarian tumor ascites. Administration of anti-SR-A immunotoxin to mice challenged with peritoneal ID8 tumors substantially inhibits peritoneal tumor burden and ascites accumulation. Additionally, VLCs harvested from the peritoneum of tumor bearing mice are immunosuppressive cells. Similar to a variety of tumor infiltrating leukocytes, arginase 1 (ARG1) activity is necessary for VLCs immunosuppression. Moreover, ID8 cell growth induces in vivo immunosuppression in splenocytes, and CD11b+ cells mediate this suppression. The elimination of SR-A+ cells from the peritoneum of tumor bearing mice relives this suppression. Extending these results we demonstrate that the protective anti-tumor effect of VLC elimination does not occur when CD8+ T Cells are concomitantly depleted. Further more, using a genetic model, short-term depletion of VLCs blocks immunosuppression and allows for efficacious vaccination against model antigens in tumor bearing mice. This study further delineates the interplay between tumor growth and the immune system and has implications on the design of cancer immunotherapies. The immunosuppressive phenotype of VLCs places them among the growing number of suppressive tumor associated leukocytes. These data add to the body of literature describing the interactions between cancerous lesions and the immune system.
Description	x, 199 leaves : ill. ; 28 cm.
Format	application/pdf
Advisor	Brent L Berwin Jose R Conejo-Garcia, Henry N Higgs, Kelvin P Lee
Subject	Leucocytes -- Pathophysiology. Immunosuppression. Ovaries -- Cancer -- Pathophysiology. Peritoneum -- Cancer -- Pathophysiology. Medical Term Ovarian Neoplasms -- physiopathology. Peritoneal Neoplasms -- physiopathology.
College	Dartmouth Medical School -- Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.300

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	The Function of Tumor Associated Leukocytes in Ovarian Cancer Growth A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Microbiology and Immunology by S. Peter G. Bak DARTMOUTH COLLEGE Hanover, New Hampshire July 1st, 2009 Examining Committee: ____________________________ (Chair) Brent Berwin, Ph.D. ____________________________ Jose Conejo-Garcia, M.D., Ph.D. ____________________________ Henry Higgs, Ph.D. ____________________________ ____________________________ Kelvin Lee, M.D. Brian W. Pogue, Ph.D. Dean of Graduate Studies

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