Suppression,subversion and escape: the role of regulatory T cells in cancer progression

Regulatory T cells (T_regs) are crucial in mediating immune homeostasis and promoting the establishment and maintenance of peripheral tolerance. However, in the context of cancer their role is more complex, and they are thought to contribute to the progress of many tumours. As cancer cells express both self‐ and tumour‐associated antigens, T_regs are key to dampening effector cell responses, and therefore represent one of the main obstacles to effective anti‐tumour responses. Suppression mechanisms employed by T_regs are thought to contribute significantly to the failure of current therapies that rely on induction or potentiation of anti‐tumour responses. This review will focus on the current evidence supporting the central role of T_regs in establishing tumour‐specific tolerance and promoting cancer escape. We outline the mechanisms underlying their suppressive function and discuss the potential routes of T_regs accumulation within the tumour, including enhanced recruitment, in‐situ or local proliferation, and de‐novo differentiation. In addition, we review some of the cancer treatment strategies that act, at least in part, to eliminate or interfere with the function of T_regs. The role of T_regs is being recognized increasingly in cancer, and controlling the function of these suppressive cells in the tumour microenvironment without compromising peripheral tolerance represents a significant challenge for cancer therapies.     

Robustness of a Combined Modified Dixon and PROPELLER Sequence with Two Interleaved Echoes in Clinical Head and Neck MRI

Purpose:The combination of modified Dixon (mDixon) and periodically rotated overlapping parallel lines with enhanced reconstruction sequence with two interleaved echoes, which promotes uniform fat-suppression and motion insensitivity, has recently become available for commercial magnetic resonance imaging (MRI) scanners. To compare the robustness of this combination sequence with that of standard Cartesian mDixon sequence for fat-suppressed T₂-weighted imaging in clinical head and neck MRI.Methods:Fifty patients with head and neck tumors were involved this study. All patients underwent MRI using both the combination and standard sequences. Two radiologists independently scored motion artifacts and water–fat separation error using a 4-point scale (1, unacceptable; 4, excellent). Furthermore, comprehensive comparative evaluation was performed using a 5-point scale (1, substantially inferior; 5, substantially superior). Data were statistically analyzed using the Wilcoxon signed-rank test.Results:In the motion artifact assessment, ratings of 3 or 4 points were assigned to 45% (observer-1, 58.0%; observer-2, 32.0%) and 97% (100%; 94.0%) of images for the standard and combination sequences, respectively (P < 0.001). For the water–fat separation error assessment, ratings of 3 or 4 points were assigned to 100% (100%; 100%) and 85% (84.0%; 86.0%) of images, respectively (P < 0.001). In the comprehensive evaluation, of the 100 cases (observer-1, 50; observer-2, 50), 96 were rated at four or five points. In cases with slight or no motion artifacts and water–fat separation errors, the combination sequence was superior to the standard sequence in term of noise and sharpness, and equal in terms of contrast.Conclusion:Although water–fat separation errors increased significantly in the combination sequence, most of these were acceptable. The significantly decreased motion artifacts in the combination sequence significantly improved image quality overall.     

Cancer‐generated lactic acid: a regulatory,immunosuppressive metabolite?

The common preference of cancers for lactic acid‐generating metabolic energy pathways has led to proposals that their reprogrammed metabolism confers growth advantages such as decreased susceptibility to hypoxic stress. Recent observations, however, suggest that it generates a novel way for cancer survival. There is increasing evidence that cancers can escape immune destruction by suppressing the anti‐cancer immune response through maintaining a relatively low pH in their micro‐environment. Tumours achieve this by regulating lactic acid secretion via modification of glucose/glutamine metabolisms. We propose that the maintenance by cancers of a relatively low pH in their micro‐environment, via regulation of their lactic acid secretion through selective modification of their energy metabolism, is another major mechanism by which cancers can suppress the anti‐cancer immune response. Cancer‐generated lactic acid could thus be viewed as a critical, immunosuppressive metabolite in the tumour micro-environment rather than a ‘waste product’. This paradigm shift can have major impact on therapeutic strategy development. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

A 14-mer Peptide from HSP70 Protein is the Critical Epitope Which Enhances NK Activity Against Tumor Cells in vivo

Heat shock protein 70 (Hsp70) has been found to play key roles in tumor immunity due its chaperone function of binding antigenic peptides. Here we report it can also stimulate NK cells in vivo, which is another role in Hsp70s' anti-tumor response. Injecting Hsp70 into mice increased splenic NK cell populations, which may be reason for anti-tumor effect of Hsp70. The Hsp70 14-mer peptide (aa450–463, TRD) was identified as the critical epitope for this stimulatory activity. It was the murine Hsp70 14-mer peptide TRD instead of the corresponding human Hsp70 14-mer peptide TKD that functioned in the mouse experimental model.     

Immunomodulatory aspects in the progression and treatment of oral malignancy

Inflammation substantially affects the risk of oral malignancy. Pro-inflammatory cytokine, interferon (IFN)-γ, confers anti-tumor activity using several different mechanisms. Conversely, higher expression of interleukin (IL)-17 is associated with worse prognosis. Monocyte chemotactic protein (MCP)-1 correlates positively with poor long-term survival of head and neck squamous cell carcinoma (HNSCC) patients. IL-1α affects cancer associated fibroblasts and macrophages, and promote several malignant phenotypes including immune suppression. Some anti-inflammatory cytokines, including IL-10 and transforming growth factor (TGF)-β, relate to pro-tumoral activities.Among immune checkpoint modulators, programmed death (PD-)1 and PD-ligand (L)1 facilitate oral squamous cell carcinoma (OSCC) cell evasion from immune surveillance, and the expression status of these has a prognostic value.OSCCs contain tumor associated macrophages (TAMs) as major stromal cells of their tumor microenvironment. Among the two distinctive states, M2 macrophages support tumor invasion, metastasis and immune suppression. Crosstalk between TAMs and OSCC or cancer-associated fibroblasts (CAF) plays an important role in the progression of OSCC.Clinical trials with blocking antibodies against IL-1α or melanoma-associated antigens have been reported as therapeutic approaches against OSCCs. The most promising approach activating antitumor immunity is the blockade of PD-1/PD-L1 axis. Manipulating the polarization of pro-tumorigenic macrophages has been reported as a novel therapeutic approach.