T cell-based cancer immunotherapy depends on the ability of blood-borne T cells to gain access to malignant tissues in order to initiate tumor-target destruction. While expansion of the pool of circulating effector T cells can be achieved therapeutically by adoptive T cell transfer, the overall success of immunotherapy strategies has been limited. Our studies have defined a paucity of trafficking molecules on tumor microvessels that are required for T cell entry into the tumor microenvironment. However, we have discovered that the tumor microenvironment can be exploited favorably by systemic thermal therapy (STT) to increase the adhesive properties of vascular endothelial cells that serve as gateways to tumor tissues. These observations lead us to hypothesize that systemic thermal therapy (STT) can improve the efficacy of adoptive T cell therapy by targeting the delivery of cytolytic T lymphocytes to primary and metastatic sites of tumor growth. The proposed studies are formulated on the basis of the identification of a novel lymphocyte-endothelial-interleukin-6 (IL-6) axis in murine tumor models that mediates the proadhesive activities of STT. A major adhesive target of STT is the vascular gatekeeper, intercellular adhesion molecule-1 (ICAM-1), which supports both firm arrest of T cells on vessel walls and transendothelial migration.
In Aim 1 we plan to build on our previous findings to determine if STT acts through an IL-6-dependent mechanism to modify additional trafficking molecules (adhesion receptors, chemokines) that recruit T cells in a murine B16 melanoma model of adoptive immunotherapy. Complementary in situ imaging studies will investigate the contribution of endogenous human IL-6 in mobilizing adoptively transferred T cells in a preclinical xenograft model of human melanoma.
In Aim 2 We will test the hypothesis that preconditioning of the host tissue environment by transient lymphodepletion amplifies the effects of STT on the trafficking of effector T cells to murine melanoma tumor tissues. The combinatorial effects of this multimodality therapy on ICAM-1-dependent entry of CD8 effector T cells in tumor tissues will be defined using antibody-blocking strategies and adhesion-deficient mice. A causal relationship between early T cell entry into tumor tissues and tumor cell apoptosis will be evaluated.
Aim 3 will test the hypothesis that enhancement of the local chemokine availability on the tumor vascular landscape can collaborate with STT to enhance CD8 T cell trafficking to tumor tissues during adoptive transfer. The requirement for the chemokine/chemokine receptor pair, CXCL10/CXCR3, in mediating the transition of T cells from initial rolling interactions to ICAM-1-dependent firm arrest in tumor vessels will be probed using a sustained-release microsphere system for delivery of CXCL10. The proposed studies are expected to provide new insights into mechanisms of T cell delivery to the tumor microenvironment and offer a conceptual basis for novel therapeutic strategies in cancer immunotherapy.

Public Health Relevance

Despite considerable progress in the development of immunotherapy strategies in cancer, these therapies have had minimal overall impact and treatment options continue to be limited for advanced-stage patients. This proposal is formulated based on our findings that systemic thermal therapy is a novel approach to target the delivery of tumor-specific cytolytic T lymphocytes to the tumor microenvironment, thereby overcoming a significant barrier to T cell-based immunotherapy. The proposed studies are expected to provide needed insights into the dynamic mechanisms that underlie targeted delivery of effector T cells to the tumor microenvironment and offer a conceptual basis for novel therapeutic strategies in cancer immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Wong, Rosemary S
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Roswell Park Cancer Institute Corp
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Fisher, Daniel T; Appenheimer, Michelle M; Evans, Sharon S (2014) The two faces of IL-6 in the tumor microenvironment. Semin Immunol 26:38-47
Mikucki, Maryann E; Fisher, Daniel T; Ku, Amy W et al. (2013) Preconditioning thermal therapy: flipping the switch on IL-6 for anti-tumour immunity. Int J Hyperthermia 29:464-73
Brackett, Craig M; Muhitch, Jason B; Evans, Sharon S et al. (2013) IL-17 promotes neutrophil entry into tumor-draining lymph nodes following induction of sterile inflammation. J Immunol 191:4348-57
Fisher, Daniel T; Chen, Qing; Skitzki, Joseph J et al. (2011) IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest 121:3846-59
Fisher, Daniel T; Vardam, Trupti D; Muhitch, Jason B et al. (2010) Fine-tuning immune surveillance by fever-range thermal stress. Immunol Res 46:177-88
Skitzki, Joseph J; Repasky, Elizabeth A; Evans, Sharon S (2009) Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs 10:550-8
Evans, Sharon S; Fisher, Daniel T; Skitzki, Joseph J et al. (2008) Targeted regulation of a lymphocyte-endothelial-interleukin-6 axis by thermal stress. Int J Hyperthermia 24:67-78
Vardam, Trupti D; Zhou, Lei; Appenheimer, Michelle M et al. (2007) Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance. Cytokine 39:84-96
Appenheimer, Michelle M; Girard, Rachael A; Chen, Qing et al. (2007) Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress. Eur J Immunol 37:2856-67
Chen, Qing; Fisher, Daniel T; Clancy, Kristen A et al. (2006) Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat Immunol 7:1299-308

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