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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