The link between T cell activation and development of functionally useful tumour associated high endothelial venules

High endothelial venules (HEVs) are specialized postcapillary venules that specifically serve to recruit circulating lymphocytes to secondary lymphoid organs (SLOs) where cognate antigens can be encountered, and immune responses can be initiated. The presence of HEV-like vessels in primary human solid tumours and their association with lymphocyte infiltration and favourable clinical outcomes and response to immunotherapy have provided a rationale for therapeutically inducing these vessels in tumours for immunotherapeutic benefit. Here we specifically discuss evidence for a link between T-cell activation and development of useful tumour-associated HEV (TA-HEV). We discuss the molecular and functional features of TA-HEV, highlighting the benefits for promoting tumour immunity and the important unanswered questions that need to be addressed before TA-HEV induction can be optimized for immunotherapeutic benefit

Exploiting ECM remodelling to promote immune-mediated tumour destruction

Cancer immunotherapy represents a significant breakthrough in cancer treatment mainly due to the ability to harness the activities of cancer-specific T cells. Despite this, most cancers remain resistant to T cell attack. Many reasons have been proposed to explain this, ranging from a lack of antigenicity through to the immunosuppressive effects of the tumour microenvironment. In this review, we examine the relationship between the immune system and a key component of the tumour microenvironment, namely the extracellular matrix (ECM). Specifically, we explore the reciprocal effects of immune cells and the tumour ECM and how the processes underpinning this relationship act to either promote or restrain tumour progression

Protective Immunity Does Not Correlate with the Hierarchy of Virus-specific Cytotoxic T Cell Responses to Naturally Processed Peptides

Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) stimulates major histocompatibility complex class I–restricted cytotoxic T cells (CTLs), which normally resolve the infection. Three peptide epitopes derived from LCMV have been shown to bind the mouse class I molecule H-2 Db and to stimulate CTL responses in LCMV-infected mice. This report describes the identity and abundance of each CTL epitope after their elution from LCMV-infected cells. Based on this information, peptide abundance was found to correlate with the magnitude of each CTL response generated after infection with LCMV. Subsequent experiments, performed to determine the antiviral capacity of each CTL specificity, indicate that the quantitative hierarchy of CTL activity does not correlate with the ability to protect against LCMV infection. This report, therefore, indicates that immunodominant epitopes should be defined, not only by the strength of the CTL response that they stimulate, but also by the ability of the CTLs to protect against infection

Sequential targeting of PI3Kδ and LAG3 as an effective anti-cancer approach

Emerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling successful tumour control in all treated mice

Tracking the kinetics of intrahepatic immune responses by repeated fine needle aspiration of the liver

Liver disease is an increasing global health burden. The final sequalae of cirrhosis, liver failure and hepatocellular carcinoma are often the result of inflammation driven by intrahepatic lymphocytes. Accurate assessment of organ-specific diseases ideally employs tissue sampling though this is rarely performed. Here we report our experiences of utilising repeated fine needle aspirations (FNAs) to assess liver-derived leukocytes. In 88 patient samples, we obtained a mean of 36,959 lymphocytes from each FNA-derived biopsy (SD 22,319 cells, range 5034–91,242 cells) measured by flow cytometry. This quick technique required minimal analgesia compared to liver biopsy (p = 0.03); was well tolerated and safe, and hence repeated sampling up to 3 times within a week was feasible. We detail the technique to rapidly derive a single cell suspension suitable for multiparameter flow cytometry analysis. Finally we illustrate the importance of organ-derived sampling by showing that natural killer (NK) cells from FNA samples have a markedly altered phenotype compared to those assessed in peripheral blood. In combination these data validate FNA as a powerful and well-tolerated method of sampling intrahepatic lymphocytes to study the immunology of acute and chronic liver diseases

Home sweet home: The tumor microenvironment as a haven for regulatory T cells

CD4+Foxp3+ regulatory T cells (Tregs) have a fundamental role in maintaining immune balance by preventing autoreactivity and immune-mediated pathology. However this role of Tregs extends to suppression of anti-tumor immune responses and remains a major obstacle in the development of anti-cancer vaccines and immunotherapies. This feature of Treg activity is exacerbated by the discovery that Treg frequencies are not only elevated in the blood of cancer patients, but are also significantly enriched within tumors in comparison to other sites. These observations have sparked off the quest to understand the processes through which Tregs become elevated in cancer-bearing hosts and to identify the specific mechanisms leading to their accumulation within the tumor microenvironment. This manuscript reviews the evidence for specific mechanisms of intra-tumoral Treg enrichment and will discuss how this information may be utilized for the purpose of manipulating the balance of tumor-infiltrating T cells in favor of anti-tumor effector cells

Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer

Background. There is indirect evidence that T cell responses can control the metastatic spread of colorectal cancer (CRC). However, an enrichment of CD4(+)Foxp3(+) regulatory T cells (Tregs) has also been documented. Objective. To evaluate whether CRC promotes Treg activity and how this influences anti-tumour immune responses and disease progression. Methods. A longitudinal study of Treg activity on a cohort of patients was performed before and after tumour resection. Specific CD4(+) T cell responses were also measured to the tumour associated antigens carcinoembryonic antigen (CEA) and 5T4. Results. Tregs from 62 preoperative CRC patients expressed a highly significant increase in levels of Foxp3 compared to healthy age-matched controls (p=0.007), which returned to normal after surgery (p=0.0075). CD4(+) T cell responses to one or both of the tumour associated antigens, CEA and 5T4, were observed in approximately two-thirds of patients and one third of these responses were suppressed by Tregs. Strikingly, in all patients with tumour recurrence at 12 months, significant preoperative suppression was observed of tumour-specific (p=0.003) but not control CD4(+) T cell responses. Conclusion. These findings demonstrate that the presence of CRC drives the activity of Tregs and accompanying suppression of CD4(+) T cell responses to tumour-associated antigens. Suppression is associated with recurrence of tumour at 12 months, implying that Tregs contribute to disease progression. These findings offer a rationale for the manipulation of Tregs for therapeutic intervention