Preconditioning thermal therapy: Flipping the switch on IL-6 for anti-tumour immunity

Figures & data

Figure 1. T cell-based immunotherapies share a common requirement for trafficking across vascular checkpoints in tumour tissues. The direct tumouricidal activity of therapeutic interventions including dendritic cell (DC) vaccination, adoptive T cell transfer, and administration of cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors hinge on the ability of cytotoxic CD8⁺ T cells to traffic across vascular barriers (blue cells in inset) within the tumour microenvironment.

Figure 2. Thermal therapy primes tumour microvessels to support E/P-selectin-dependent and ICAM-1-dependent trafficking of CD8⁺ effector T cells. (A) Multistep adhesive interactions direct circulating T cells into tumour sites where they can kill tumour cell targets; thermally responsive adhesion events are marked by red asterisks (*). (B) STT treatment of B16-OVA tumours increased intravascular expression of ICAM-1 (red) over baseline normothermal control (NT). The landmark position of vessels in photomicrographs is shown by immunostaining for the CD31 pan-endothelial adhesion molecule (green). Histograms represent quantitative image analysis of relative immunofluorescence staining intensity of CD31 or ICAM-1 on all CD31⁺ vessels; studies were performed as described by Fisher et al. [35]. Bar, 50 μm.

Figure 3. Thermal therapy induces CD8⁺ T cell trafficking and target cell apoptosis in the tumour microenvironment. (A) Schematic for combination systemic thermal therapy (STT) and adoptive cell transfer (ACT) of tumour-specific effector CD8⁺ T cells. Experimental endpoints for analysis of CD8⁺ T cell homing and TUNEL staining of apoptotic cells in tumour cryosections as well as tumour growth control are described in a recent report [35]. (B) Administration of IL-6–neutralising monoclonal antibody (mAb) 30 min prior to STT blocked induction of CD8⁺ T cell trafficking (red) and apoptosis of intratumoural cellular targets (green). Relative values for normothermal (NT) mice are shown; nucleated cells are labelled with DAPI (blue). Left, representative photomicrographs of tumour cryosections. Bar, 50 μm. Right, quantification of intratumoural CD8⁺ T cells and TUNEL⁺ apoptotic cells per unit area of tumour tissue. *p < 0.001. (C) Thermal induction of ICAM-1-dependent CD8⁺ T cell trafficking in tumour vessels involves an IL-6 trans-signalling mechanism whereby intracellular JAK-1/2 and STAT3 activation occurs downstream of ligation of an agonistic, soluble form of the IL-6 receptor α binding subunit (sIL-6Rα) and the gp130 signal transducing subunit.

Figure 4. Collaborative intersection between thermal therapy and IL-6 in the tumour microenvironment. (A) Thermal therapy tips the balance of IL-6 activity in the tumour microenvironment from a tumour-promoting inflammatory role to an anti-tumourigenic role supporting T cell-mediated tumour immunity. (B) Outstanding questions remain regarding which chemokine/chemokine receptor interactions (inset) mediate CD8⁺ T cell trafficking at the vascular interface during heat therapy and whether clinical responses to preconditioning regimens are predicated on the presence of immunosuppressive cell subsets (inset) within the tumour microenvironment.

Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest 2011;121:3846–59

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