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CXCR3 and its cognate-chemokine expression : implications for cancer immunotherapy / by Eleanor Clancy-Thompson

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Author	Clancy-Thompson, Eleanor
Title	CXCR3 and its cognate-chemokine expression : implications for cancer immunotherapy / by Eleanor Clancy-Thompson
Date	2015
Abstract	Despite immunogenicity, melanoma-specific vaccines have demonstrated minimal clinical efficacy in patients with established disease, but enhance survival when administered in the adjuvant setting. It has been shown that T cell infiltration of melanoma is associated with enhanced clinical efficacy and is a desirable endpoint of immunotherapeutic vaccination. T cell infiltration into tumors is regulated, in part, by chemokine receptors. Therefore, we have investigated the chemokine receptor CXCR3 in three different settings. 1) The induction of CXCR3 on CD8 T cells by peptide vaccination in human patients, 2) the requirement for CXCR3 expression on CD8 T cells for the infiltration of metastatic melanoma lesions in the lungs of mice, and 3) the requirement for host CXCR3 expression for engraftment of metastatic melanoma in the lung. Our results are three-fold. 1) We determined that vaccination of a melanoma peptide vaccine in adjuvant induces tumor antigen-specific CD8 T cells that are predominantly positive for CXCR3. These cells express high levels of Tbet, IFN- ?, and IL-12R-?1, and thus maintain a phenotype that supports the infiltration and eradication of melanoma. 2) We demonstrated that CXCR3 is required for efficient infiltration of tumor-bearing lungs. Additionally, we observed temporal regulation of CXCR3-cognate chemokines with the establishment of melanoma metastases in the lung. This correlated with temporal regulation of T cell infiltration. We demonstrated that blocking adenosine signaling in the tumor microenvironment restored chemokine production and T cell infiltration in advanced metastatic lesions. 3) Host expression of CXCR3 is required for the engraftment of pulmonary melanoma metastases. We observed that CXCR3-/- mice were protected from melanoma engraftment in the lung, as early as 24 hours after tumor cell injection. We determined that a CXCR3+ host cell was mediating this differential engraftment, and determined that eliminating macrophages in C57BL/6 mice could reduce melanoma engraftment of the lung to levels seen in CXCR3-/- mice. We show that CXCR3 and its ligands play a crucial role in both immunemediated regulation, and metastatic dissemination, of melanoma. Therefore, regulation of CXCR3 expression on lymphocytes and CXCR3 ligands in the tumor microenvironment will be critical for optimizing immune-mediated therapy of melanomas (and likely other tumors).
Description	1 online resource (xix, 159 leaves) : illustrations (some color)
Format	application/pdf
College	Dartmouth College -- 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.1912

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CXCR3 and its cognate-chemokine expression : implications for cancer immunotherapy / by Eleanor Clancy-Thompson

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