Tumor–Host Immune Interactions and Dendritic Cell Dysfunction

https://doi.org/10.1016/S0065-230X(04)92002-7Get rights and content

Abstract

Several lines of evidence from recent years support the existence of cancer immunosurveillance, especially studies of natural killer (NK) cells and the IFN-γ pathway. However, immune suppression is clearly observed in cancer patients and tumor-bearing animals as well. The fact is that although cancers often elicit a vigorous immune response during the early part of their growth, the immune response is soon down-regulated, permitting progressive tumor growth. Apparently, the intrinsic plasticity of tumors allows the immune system to sculpt the immunogenic phenotypes of tumors to escape efficient immune destruction. But most evidently, several mechanisms have now been found to contribute to the failure of immune control of tumor growth. Tumor cells have a very low level of MHC class II, costimulatory molecules, and weak antigens. They also produce immune suppressive factors (VEGF, IL-10, PGE2) that exert systemic effects on immune cell function. In particular, disabled dendritic cell differentiation, maturation, migration, and function are fundamental to this defect, as they are the most potent antigen-presenting cells (APCs) of the immune system, interacting with T and B lymphocyte as well as NK cells to induce and modulate immune responses. In addition, tumors also alter host hematopoiesis and produce large numbers of immature dendritic cells, and evidence shows that these cells are directly immune suppressive. Harnessing the immune system for effective cancer therapy has remained a great challenge. DC-based vaccines, or DC-based vaccines in combination with treatments designed to improve the host immune environment, may offer hope for more effective cancer immunotherapy.

Tumor–host interactions are an important determinant of tumor behavior and response to therapy. How tumors interact with their hosts is thus a very broad and complex topic. In this chapter, we will focus on tumor–host immune interactions and the roles of dendritic cell dysfunction in tumor avoidance of host immune responses. We will survey recent findings regarding tumor immune surveillance, antitumor host immune responses, and how the immune system also functions to promote or select tumor variants with reduced immunogenicity. We will then discuss immune suppression caused by tumors, which is clearly observed in tumor-bearing animals and cancer patients. Finally, we will discuss altered dendritic cell function and differentiation in some detail, as it is likely to be one of the most fundamental mechanisms by which tumors escape immune responses.

Section snippets

Antitumor Host Immune Responses

The immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas of immunity. Theoretically, our immune system can play a protective role in tumor development by recognizing and destroying nascent transformed cells. This is evident in the greatly increased frequency of skin cancers in organ transplant patients. While this idea is generally accepted, there is a lack of convincing evidence for it in many other situations.

Immune Suppression in Cancer

Despite the new evidence supporting cancer immunosurveillance and antitumor immune responses, tumor-induced immune suppression is clearly observed in tumor-bearing animals and cancer patients. The fact is that although cancers elicit a vigorous immune response during the early part of their growth, the immune response is soon down regulated, permitting progressive tumor growth.

Many mechanisms have been found to contribute to the failure of the immune system to control tumor growth. First, tumor

Dendritic Cells In Cancer Therapy

The principle underlying the ex vivo growth or manipulation of dendritic cells for reinjection is based on the assumption that tumors fail to induce specific responses due to a failure of effective antigen presentation. Functionally competent DCs can be generated from progenitors isolated from the peripheral blood of cancer patients and cultured in vitro in the presence of the appropriate cytokines (Gilboa 1998, McArthur 1998). Dendritic cells, expanded and activated in vitro, may be effective

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