Sunday, November 20, 2016

Increased T-Regulatory Suppression Activity in Cancerous Tissue

            In an article published just last week in the journal Immunity, scientists found that human tumor-infiltrating T regulatory lymphocytes (Treg) differ from normal tissue Treg cells in mRNA and protein expression, with characteristically high suppression of effector T cells and upregulation of immune-checkpoint genes and proteins within these tumors. Treg lymphocytes have a role in immune system maintenance, downregulating the effector T cells that target specific viral or tumor cells for destruction.1 These Treg cells have a known role in autoimmune prevention, restricting the host from overproduction of effector T cells and consequential self-targeting. However, Treg cells are suspected to have a role that is beneficial for tumor development and growth, as anti-tumor T cell activity was found to be decreased upon tumor proliferation2, and depletion of Treg lymphocytes in mice was found to lead to efficient rejection of implanted tumors.3 Based on these studies, the regulatory activity of Treg cells is presumably elevated, resulting in increased immune cell suppression and subsequent tumor survival. For these reasons, in this study, scientists compared mRNA and protein expression between tumor-infiltrating and normal tissue Treg lymphocytes, looking for major differences that may be responsible for the increased suppressive activity in tumor environments.
Figure 1: Treg suppression of effector T cell proliferation in cancer tissue versus normal tissue.2 CFSE is a fluorescent cell dye used for proliferation analysis.

In order to make these comparisons, Treg samples were taken from non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) tumors, and from the adjacent healthy tissues. As seen in Figure 1, Treg cells present in tumor environments showed a much stronger suppressive ability as compared to healthy tissue Treg cells, with effector T cell proliferation substantially decreased within the cancerous tissue.2 These results are consistent with previous observations, supporting the role of Treg cells in downregulating the host immune response against tumors. The mRNA expression of these Treg cells was analyzed through RNA sequencing, which found that genes involved in immune checkpoints were upregulated in tumor-infiltrating Treg lymphocytes as compared to healthy tissue Treg cells.2 This upregulation of immune checkpoint genes is unsurprising considering the elevated activity of Treg cells in immune response suppression in tumor environments. Whole transcriptome sequencing, in combination with a form of data analysis called principal component analysis (PCA), found clear gene expression pattern differences between tumor-infiltrating and normal Treg cells2, further supporting the phenotypic differences between these cells. Protein expression analysis by flow cytometry revealed similar results, as proteins involved in Treg activity were upregulated in tumor-infiltrating Treg lymphocytes, included proteins involved in programmed cell death (PDL-1, PDL-2) and immune system regulation (IL-1R2, IL-21R).2  Both mRNA and protein expression indicated clear molecular differences between tumor-infiltrating and normal tissue Treg cells, with upregulation of immune suppression genes and proteins leading to increased Treg activity in cancerous tissues.  
            Ultimately, the role of Treg cells in the suppression of immune effector T cells in tumor environments has important and potentially practical applications for cancer therapy. As seen in previous research, removal of T-regulatory cells from mice results in efficient rejection of implanted tumors.3 The elevated suppressive ability of Treg cells in cancerous tissue is preventing normal immune system function, downregulating effector T cells that are required for targeted destruction of tumor cells. However, Treg cells are necessary immune system regulators in normal tissue, as they prevent autoimmune responses from occurring following infection or other immune system activations. For these reasons, any cancer therapy targeting Treg cells must walk a fine line, either limiting Treg targeting to cancerous tissue, or downregulating rather than depleting Treg cells, in order to prevent host-damaging autoimmunity. While far more research is required for any of these possibilities, the prospect of immune-based stem cells or progenitors could possibly be employed to replenish depleted Treg cells, if Treg cells were temporary depleted from the host in order to combat tumor survival. The research presented in this paper, however, focuses on the mRNA and protein level expression differences between normal tissue and tumor-infiltrating Treg cells, which is crucial for a better understanding of the molecular mechanism behind this increased suppressive activity. Increased understanding of this mechanism is a necessary first step for any potential cancer therapy, as knowing where and how to target these overactive Treg cells will help lead to an efficient and effective therapeutic response.

1 Unitt, E., Rushbrook, S.M., Marshall, A., Davies, S., Gibbs, P., Morris, L.S., Coleman, N., Alexander, G.J. (2005). Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41, 722-730.

2 Simone, M.D. et al. (2016). Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45, 1135-1147.

3 Liyanage, U.K, Moore, T.T., Joo, H., Tanaka, Y., Herrmann, V., Doherty, G., Drebin, J.A., Strasberg, S.M., Eberlein, T.J., Goedegebuure, P.S., Linehan, D.C. (2002). Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. Journal of Immunology 169, 2756-2761.

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