Influence of tumors on protective anti-tumor immunity and the effects of irradiation

Gemma A Foulds,Alan G Pockley,Gabriele Multhoff,Jürgen Radons,Mira Kreuzer

doi:10.3389/fonc.2013.00014

Abstract

Innate and adaptive immunity plays important roles in the development and progression of cancer and it is becoming apparent that tumors can influence the induction of potentially protective responses in a number of ways. The prevalence of immunoregulatory T cell populations in the circulation and tumors of patients with cancer is increased and the presence of these cells appears to present a major barrier to the induction of tumor immunity. One aspect of tumor-mediated immunoregulation which has received comparatively little attention is that which is directed toward natural killer (NK) cells, although evidence that the phenotype and function of NK cell populations are modified in patients with cancer is accumulating. Although the precise mechanisms underlying these localized and systemic immunoregulatory effects remain unclear, tumor-derived factors appear, in part at least, to be involved. The effects could be manifested by an altered function and/or via an influence on the migratory properties of individual cell subsets. A better insight into endogenous immunoregulatory mechanisms and the capacity of tumors to modify the phenotype and function of innate and adaptive immune cells might assist the development of new immunotherapeutic approaches and improve the management of patients with cancer. This article reviews current knowledge relating to the influence of tumors on protective anti-tumor immunity and considers the potential influence that radiation-induced effects might have on the prevalence, phenotype, and function of innate and adaptive immune cells in patients with cancer.

Highlights

For many years, the paradigm on which the majority of immunotherapeutic approaches for the treatment of cancer has been based, is that adaptive immune responses to tumors are similar to those that are induced in the generation of immunity to infectious pathogens
Tumor-derived cytokines such as IL-10 and TGF-β might protect against the development of anti-tumor immunity by influencing the functional capacity of antigen presenting cells (APCs) such as dendritic cells (DCs), and by promoting the generation/differentiation/expansion of immunoregulatory T cell populations which have the capacity to control and prevent immune responses (Ghiringhelli et al, 2005b; Liu et al, 2007; Mahnke et al, 2007a; Biollaz et al, 2009; Conroy et al, 2012; Multhoff and Radons, 2012)
In vivo experiments using a murine model of mammary carcinoma have demonstrated that radiotherapy-induced expression of the chemokine CXCL16 is an important mechanism which mediates the infiltration of CD8+ T effector cells following treatment, as the recruitment of CD8+ T cells and responsiveness to treatment are reduced in mice that are deficient for its ligand (CXCR6) (Matsumura et al, 2008)

Summary

Introduction

The paradigm on which the majority of immunotherapeutic approaches for the treatment of cancer has been based, is that adaptive immune responses to tumors are similar to those that are induced in the generation of immunity to infectious pathogens. The evidence that the depletion of CD4+CD25high Treg cells enhances the capacity to induce cellular and humoral immunity to Her-2 which is expressed on primary and metastatic breast cancer cells (Fulton et al, 2006) confirms the importance of these cells and highlights the importance of improving our understanding of the influence of the breast tumor microenvironment on protective innate and adaptive anti-tumor immunity.

Results

Conclusion