Immunotherapy: a useful strategy to help combat multidrug resistance

Abstract

Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct for other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic agents, capitalization on other immune properties of MDR positive cells, or conditional immunotoxins expressed under MDR control. Additional insights into the immunogenic potential of some cytotoxic agents can also be brought to bear on these strategies. This review will highlight key concepts in cancer immunotherapy and illustrate immune principles and strategies that have been or could be used to help destroy MDR positive tumor cells, either alone or in rational combinations.

Figure 1

The critical elements of anti-tumor immunity. Tumors express tumor antigens that should be objects of immune attack (1). Antigen presenting cells (2) take up antigen, and process and present them to antigen-specific cells, including CD4⁺ and CD8⁺ T lymphocytes (3), that should lead to immune elimination of the tumor (4). Cytokines, such as IL-12, and surface molecules such as CD80 and CD86 provide signals that should promote this tumor-specific immune response. Antigen presenting cells such as dendritic cells, and other non-specific cells suck as natural killer cells and macrophages collectively comprise the innate immune system. Adaptive immunity includes antigen-specific cells such as CD4⁺ and CD8⁺ T cells, and B cells (not shown). Despite this sophisticated immune response, which does occur in most cancers, immune elimination does not occur owing to the immune dysfunction shown in figure 2. Figure adapted from (Curiel, 2007).

Figure 2

Critical elements of tumor-associated immune dysfunction. Although anti-tumor immunity is elicited according to the scheme outlined in figure 1, and shown in the top half of this figure, active tumor-driven immune dysfunction (boxed portion in bottom half of the figure) thwarts immune cancer elimination. Antigen presenting cells, which in the top half can activate tumor-specific immunity, can also elicit dysfunctional immune cells that turn anti-tumor immunity off, or inhibit it through subversion by tumor factors. Factors responsible for this dysfunction can derive from the tumor itself, or from local stroma or immune cells. These agents include immune suppressive vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β and interleukin (IL)-10. These molecules can directly inhibit immunity, such as the ability of TGF-β, IL-10 or VEGF to inhibit T cell activation, or can indirectly elicit other dysfunctional cells. In this latter instance, tumor IL-10 or VEGF can promote antigen presenting cells to express B7-H1, an immune molecule that can directly inhibit T cells, or promote generation of regulatory T cells (Tregs) that inhibit anti-tumor immunity. Novel strategies to overcome these complex and potent tumor-driven active defenses against anti-tumor immunity represent major new opportunities to improve the efficacy of anti-tumor immunotherapy. Figure adapted from (Curiel, 2007).