Cancer and the Immune System: Basic Concepts and Targets for Intervention

Abstract

A number of consensuses regarding cancer immunology have recently emerged from both preclinical immunotherapy models and analysis of cancer patients. First and foremost, the natural state of endogenous tumor reactive T cells is characterized by general hyporesponsiveness or anergy. This is likely due to a number of mechanisms that tumors use to induce tolerance as they develop. While many of the newer generation vaccines can effectively transfer antigen to and activate dendritic cells, T-cell tolerance remains a major barrier that is difficult to overcome by vaccination alone. Preclinical models demonstrate that for poorly immunogenic tumors, once tolerance has been established, therapeutic vaccines alone are ineffective at curing animals with a significant established tumor burden. However, combination strategies of vaccination together with inhibitors of immunologic checkpoints and agonists for co-stimulatory pathways are proving capable of overcoming tolerance and generating significant anti-tumor responses even in cases of established metastatic cancer.

Figure 1

The balance between immune surveillance, resistance and tolerance. Transformation of normal cells to cancer cells involves the creation of true neoantigens due to mutation, as well as up-regulation of self-antigens due to epigenetic forces. Successful immune surveillance of tumors based on recognition of these tumor-specific antigens would lead to tumor elimination at early stages. Clinically relevant tumor survival and progression requires that tumors develop resistance mechanisms that inhibit tumor-specific immune responses to kill tumor cells. Alternatively, if the tumor develops mechanisms to induce immune tolerance to its antigens, anti-tumor effecter responses do not develop. Evidence is accumulating that tumors actively develop immune resistance mechanisms and immune tolerance mechanisms to survive despite displaying antigens capable of recognition by the immune system.

Figure 2

Dendritic cells (DC) can either activate adaptive immunity or tolerize T cells depending on their state of maturation. DC progenitors develop from hematopoietic (bone marrow–derived) progenitors under the influence of various cytokines, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF). Under circumstances of microbial infection, specific pathogen-associated molecular patterns (termed PAMPs) engage pattern recognition receptors (PAMPs), leading to release of pro-inflammatory danger signals that induce DC maturation. DC maturation leads to up-regulation of co-stimulatory molecules, MHC and chemokines that result in activation of T cells to effecter cells (right side of figure). In the absence of these “danger signals”, DCs follow a default pathway (left side of figure) in which they become “tolerizing DCs” that present antigen to T cells in the absence of co-stimulatory signals. This represents a steady-state pathway for continuous presentation of self-antigens. The consequence is that these T cells are turned off (anergy), inducing tolerance.

Figure 3

The hostile immune microenvironment of the tumor. Activation of oncogenic pathways and inactivation of tumor-suppressor pathways in the tumor lead to a cascade of molecular and cellular processes in the tumor microenviroment that block the killing function of innate immune effectors such as NK cells and granulocytes and block DC maturation. In addition, multiple cell membrane molecules such as IL-10, TGF-β, B7-H1, and B7-H4 are up-regulated. These molecules bind to receptors that inhibit T-cell effector function. Immature myeloid cells (iMC) produce nitric oxide (NO) that inhibits T cells and immature plasmacytoid DC (iPDC) produce indoleamine dioxygenase (IDO), which depletes tryptophan. Regulatory T cells also accumulate in the tumor microenvironment, further blunting anti-tumor T-cell responses.