Given the recalcitrant nature of melanoma to conventional therapies, there exists a critical need for successful clinical immunotherapy to treat metastatic melanoma. The objective of most clinical immunotherapy trials has been to generate maximal numbers of circulating tumor- specific cytotoxic T lymphocytes (CTL), predicated on the notion that """"""""more is better."""""""" However, the correlation between magnitude of vaccine-induced CD8+ T cells and the objective clinical responses remains weak, suggesting that the inefficacy of immune therapy results from the qualitative failure of vaccine-induced T cells to efficiently activate, infiltrate tumor, and develop robust memory populations. Therefore, we have examined several qualitative aspects of tumor Ag-specific T cells from melanoma patients that have been vaccinated with multiple melanocyte differentiation protein-derived antigens in an adjuvant setting. We demonstrated a significant association between the expression of CXCR3 by circulating tumor-specific CD8+ T cells and the maintenance of disease-free status or survival, suggesting either that CXCR3 expression a) is functionally required for the T cell-mediated immunologic control of metastatic tumors, or b) serves as a marker of qualitatively-superior anti-tumor T cells. In the present proposal, we delineate three aims that will expand upon our initial findings and evaluate the mechanisms by which CXCR3 and its biological axis of molecules act to enhance immune-mediated tumor control. Specifically, we will relate CXCR3 expression in the human CD8 compartment to 1) immunization-induced polarization phenotype;2) anti-tumor functionality;3) and access to metastatic tumor compartments. We will use human tissues and samples for correlative studies and mouse models for mechanistic studies. Key deliverables of this research will include basic science knowledge with translational potential, including: 1) enhanced understanding of the regulation of CXCR3 expression and T cell polarization in human CD8+ T cells;2) evaluation of the prognostic utility of CXCR3 expression as a marker of vaccine response and means to prospectively evaluate patient-specific response potential;and 3) new immunologic targets for intervention, so as to optimize the therapeutic potential of immunogenic vaccines.

Public Health Relevance

We will evaluate the phenotype of vaccine-activated CD8+ cells in patients with metastatic melanoma, and then correlate qualitative functional aspects of these cells with clinical outcomes to determine the optimal type of T cell for rejection and control of cancer. We will also evaluate the phenotype of CD8+ T cells that infiltrate metastatic melanomas in human and use mouse models to evaluate the molecular and cellular mechanisms that govern T cell migration. Collectively, these studies will make new observations about the fundamental biology of T cell activation and migration in humans and establish the basis to optimize cancer vaccines by enhancing T cell infiltration of metastatic melanomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134799-02
Application #
7807063
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2009-05-01
Project End
2014-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$314,363
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Butler, Kiah L; Clancy-Thompson, Eleanor; Mullins, David W (2017) CXCR3+ monocytes/macrophages are required for establishment of pulmonary metastases. Sci Rep 7:45593
Whipple, Chery A; Boni, Andrea; Fisher, Jan L et al. (2016) The mitogen-activated protein kinase pathway plays a critical role in regulating immunological properties of BRAF mutant cutaneous melanoma cells. Melanoma Res 26:223-35
Mauldin, Ileana S; Wages, Nolan A; Stowman, Anne M et al. (2016) Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases. Cancer Immunol Immunother 65:1189-99
Mauldin, Ileana S; Wages, Nolan A; Stowman, Anne M et al. (2016) Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases. Cancer Immunol Immunother 65:1201-12
Jenkins, Molly H; Croteau, Walburga; Mullins, David W et al. (2015) The BRAF(V600E) inhibitor, PLX4032, increases type I collagen synthesis in melanoma cells. Matrix Biol 48:66-77
Jenkins, Molly H; Brinckerhoff, Constance E; Mullins, David W (2015) CXCR3 signaling in BRAFWT melanoma increases IL-8 expression and tumorigenicity. PLoS One 10:e0121140
Clancy-Thompson, Eleanor; Perekslis, Thomas J; Croteau, Walburga et al. (2015) Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease. Cancer Immunol Res 3:956-67
Jenkins, Molly H; Steinberg, Shannon M; Alexander, Matthew P et al. (2014) Multiple murine BRaf(V600E) melanoma cell lines with sensitivity to PLX4032. Pigment Cell Melanoma Res 27:495-501
Steinberg, Shannon M; Zhang, Peisheng; Malik, Brian T et al. (2014) BRAF inhibition alleviates immune suppression in murine autochthonous melanoma. Cancer Immunol Res 2:1044-50
Baird, Jason R; Byrne, Katelyn T; Lizotte, Patrick H et al. (2013) Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge. J Immunol 190:469-78

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