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2016 ; 22
(8
): 1856-64
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Reversing T-cell Dysfunction and Exhaustion in Cancer
#MMPMID27084739
Zarour HM
Clin Cancer Res
2016[Apr]; 22
(8
): 1856-64
PMID27084739
show ga
In the context of chronic antigen exposure in chronic viral infections and
cancer, T cells become exhausted/dysfunctional. These exhausted T cells exhibit
defective proliferative capacities and cytokine production, but are not totally
inert and may exert lytic functions. Importantly, exhausted T cells upregulate
multiple inhibitory receptors/immune checkpoints that bind to their ligands
expressed by tumor cells and antigen-presenting cells in the tumor
microenvironment (TME). Immune checkpoint blockades with anti-CTL antigen 4
(CTLA-4) and/or anti-programmed death 1 (PD-1) mAbs successfully reinvigorate
tumor-infiltrating T lymphocytes and provide persistent clinical benefits to a
large number of patients with advanced cancer. This great and long-awaited
success for the immunotherapy of cancer has infused considerable enthusiasm in
the field of oncology and fostered the development of combinatorial strategies to
target the multiple mechanisms of tumor-induced T-cell dysfunction. Here, we
review the critical immunoregulatory mechanisms driving T-cell exhaustion in the
TME. We also discuss the development of promising combinatorial immunotherapies
to counteract the mechanisms of tumor-induced T-cell dysfunction to improve the
clinical efficacy of current immune checkpoint blockades. As our understanding of
the mechanisms supporting tumor-induced T-cell dysfunction improves based upon
preclinical and clinical studies, we expect that novel combinatorial
immunotherapies will emerge to improve the clinical outcome of patients with
advanced cancers.
|Animals
[MESH]
|Antibodies, Monoclonal/pharmacology/therapeutic use
[MESH]
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