Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms

Abstract

Although numerous immunotherapeutic strategies have been studied in patients with cancer, consistent induction of clinical responses remains a formidable challenge. Cancer vaccines are often successful at generating elevated numbers of tumor-specific T lymphocytes in peripheral blood, however, despite this, tumors usually continue to grow unabated. Recent evidence suggests that endogenous regulatory cells, known to play a major role in the induction of immune tolerance to self and prevention of autoimmunity, as well as suppressive myeloid cells invoked in the tumor-bearing state, may be largely responsible for preventing effective antitumor immune responses. This review will focus on the major regulatory cell subtypes, including CD4 + CD25 + T-regulatory cells, type 1regulatoryTcells, natural killerTcells, and immature myeloid cells. Studies in humans and in animal models have shown a role for all of these cells in tumor progression, although the mechanisms by which they act to suppress immunity remain largely undefined. Elucidation of the dominant molecular mechanisms mediating immune suppression in vivo will allow more precise targeting of the relevant regulatory cell populations, as well as the development of novel strategies and clinical reagents that will directly block molecules that induce the suppression of antitumor immunity.

Fas Signal Promotes Lung Cancer Growth by Recruiting Myeloid-Derived Suppressor Cells via Cancer Cell-Derived PGE2

“…Therefore, accumulation of MDSC and Treg in tumor tissue is crucial for tumor immune escape and supposed to be the target of immunotherapy (11). However, little is known about the natural signals in the tumor microenvironment responsible for inducing accumulation and maintaining residence of MDSC and Treg cells in the tumor tissues.…”

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

“…In addition to CD25 depletion and CTLA4 blockade, other approaches, including anti-GITR antibody therapy (Ko et al, 2005), antibody blockade of PD-1 (Iwai et al, 2002;Curiel et al, 2003;Hirano et al, 2005) and neutralization of immunosuppressive cytokines, such as IL-10, TGF-b, IL-13 and vascular endothelial growth factor (Lizee et al, 2006), have been assessed for their ability to reverse Treg cell-mediated suppression of antitumour responses. However, it is likely that such non-targeted approaches will share some or all of the problems associated with CD25 depletion and anti-CTLA-4 treatment.…”

Tumour–stroma interactions in colorectal cancer: converging on β-catenin activation and cancer stemness

“…Several other tumour-infiltrating immune cells have been reported to support tumour growth, including tumour-associated macrophages, and immature myeloid and dendritic cells (Lizee et al, 2006). Also, it has been reported that specific functional aspects of innate immune cells are pivotal for intestinal homeostasis, inflammation, and tumorigenesis.…”