Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Abstract
There is much promise in the use of immunotherapy for the treatment of cancer. Approaches such as those using antibodies or adoptive cell transfer can mediate complete tumor regression in a proportion of patients. However, the tumor microenvironment can inhibit immune responses leading to ineffective or suboptimal responses of tumors to immunotherapy in the majority of cases. As our knowledge of the tumor microenvironment increases, many strategies are emerging for changing the immunosuppressive nature of the tumor toward a microenvironment able to support immunity. These strategies aim to enhance the ability of immunotherapies to initiate effective immune responses able to destroy tumors. In this article, we review approaches that use immunomodulators specifically to modify the tumor microenvironment, and their use in combination with other immune-based strategies for cancer therapy.

Keywords: immunotherapy, tumor microenvironment, regulatory T cells, macrophages, immunosuppression


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782527/

Introduction
Immunotherapy holds much promise for the treatment of cancer. A wide variety of approaches have been implemented in order to stimulate a range of immune activities including innate and adaptive components. Strategies include the use of immunomodulatory antibodies, vaccines and adoptive cell transfer. Notable clinical successes include the use of the immune check-point inhibitor, ipilimumab1 for melanoma, and rituximab targeting CD20 for lymphoma.2 Adoptive immunotherapy, involving transfer of ex vivo activated autologous T cells, is also showing promise for the treatment of melanoma.3

However, most immunotherapeutic approaches on their own are of limited value against the majority of malignancies. Reasons for this limited success include immune regulation mediated by cancer cells and leukocyte populations through a variety of cell-expressed and secreted molecules. In many cases, immune regulation occurs locally within the tumor, leading to an ineffectual or suppressed antitumor response.

Tumors are not just a mass of proliferating genetically abnormal cells, but they are now well defined as a heterogeneous and structurally complex tissue. Malignant tumor cells can recruit a variety of cell types, including fibroblasts, immune inflammatory cells, and endothelial cells, through production and secretion of stimulatory growth factors and cytokines.4 This assortment of cells and molecules together comprises the tumor microenvironment.

Antitumor immunity within the tumor microenvironment can be suppressed by a variety of tumor infiltrating leukocytes, including regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and alternatively activated (type 2) macrophages (M2).5-7 Mechanisms employed by these cell types to suppress effective immunity include secretion of cytokines such as IL-10 and TGF-β, and expression of inhibitory receptors such as CTLA-4 and PD-L1. Secretion of amino acid-depleting enzymes including arginase and IDO by these cell types in the microenvironment can also negatively impact on tumor immunity.

In addition to these effects mediated by infiltrating cells, tumor cells themselves can actively inhibit immunity through a number of mechanisms. Malignant cells can block T cell function through secretion of soluble forms of ligands for effector molecules, as reported for shed ligands of NKG2D; MICA and MICB.8 Additionally, cytokines released by tumor cells, such as VEGF and TGF-β can inhibit T cell recognition and destruction of malignant cells.9 IL-10 as well, can skew T cell responses toward a type 2 immune response that is less effective against tumor cells.10 Other secreted factors such as galectins can also impede T cell activity and survival.11

Many of these regulatory mechanisms can occur concurrently within the tumor microenvironment resulting in multiple redundant levels of immune suppression, which reduces the effectiveness of immunotherapy. Not surprisingly then, the tumor microenvironment can impede immunotherapy, and approaches to specifically reduce immune suppression within the tumor microenvironment are gaining momentum as a companion to additional immunotherapy. This review focuses on immune-based strategies to change the microenvironment to enable the effectiveness of immunotherapy, with discussion largely restricted to studies that demonstrate changes to the tumor microenvironment and synergy between that and additional immunotherapy.

* “The innate and adaptive immune systems”

http://missinglink.ucsf.edu/lm/immunolo ... obj02.html

* Introduction to Immunology Tutorial

http://www.biology.arizona.edu/immunolo ... page3.html