The Role of the Immune System in Fighting Cancer

The idea that the immune system can recognize and even eradicate tumors (now termed "immunosurveillance") was first proposed nearly a century ago in 1909.²⁰ In general, immunity is thought to play a minor role in protecting against most solid tumors (except those associated with viral infection) because many of the mechanisms designed to produce self-tolerance and protect against autoimmunity also protect tumor cells from becoming targeted by the adaptive immune system.^2,16,21

Nonetheless, evidence continues to accumulate to suggest that the human immune system does mount a response against tumor cells. Evidence supporting immunosurveillance in humans includes higher incidence of cancers (including nonviral cancers) in immunosuppressed transplant recipients compared with age-matched immunocompetent persons, demonstration of innate and adaptive immune responses in tumors of cancer patients, and the finding that tumor-infiltrating lymphocytes are a positive prognostic factor in some cancers.²² In melanoma, for example, the presence of tumor-infiltrating lymphocytes is associated with longer disease-free survival,²³ and in rare cases, the immune response has been shown to produce spontaneous regression of melanoma, including metastatic disease.²⁴ Unfortunately, in the vast majority of cases, the immune response is insufficient to result in complete tumor rejection. However, understanding of this response is fueling research into development of immunotherapies that manipulate the immune system in ways to improve its ability to fight cancer.

It is now known that many tumor cells—melanoma being the best studied—express antigens that are recognized by immune cells.^21,25 These antigens may be uniquely expressed by tumor cells or they may be proteins expressed by normal cells but overexpressed by tumor cells.²⁴ Altogether, immunologists have now found thousands of molecules expressed by cancer cells that may be targets for the immune system. These antigens are categorized according to their expression patterns as either nonmutated self-antigens or mutated gene products, both of which can be recognized by CD8+ and CD4+ T-cells (Table 1).^22,25-29

Table 1. Classification of Tumor Antigens Recognized by T-Cells.

It has been confirmed both in vitro and in vivo that T-cells can recognize tumor antigens (Figure 4³⁰), tumor-infiltrating lymphocytes (TILs) have been isolated from human solid tumors, and adoptive transfer of these TILs can mediate objective clinical response.^31,32 Most of these antigens are presented directly by tumor cells via MHC class I molecules.³³ However, T-cells may also be activated indirectly by tumor antigens or other antigens presented on class II MHC molecules of antigen-presenting cells.³¹ Dendritic cells can also cross-present tumor antigen on class I MHC. In addition, melanoma cells (but apparently not other tumor types) may constitutively express class II MHC.²⁵

Figure 4. Human T-Cell Attacking Fibroblast Tumor Cells (SEM x 4000).³⁰

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Copyright Dennis Kunkel Microscopy, Inc.

Although B-cells are thought to play less of a role than T-cells in fighting cancer, it has been shown through various in vitro methods that antibodies produced by tumor-infiltrating B-cells do target tumor cells.³⁴ Furthermore, antibodies may directly or indirectly play a role in facilitating T-cell activation, although this is controversial.¹⁷ Preclinical data strongly support this concept, which may explain the effectiveness of some antibody targeted therapies.³⁴ Other antitumor effects of B-cells may include complement fixation, as well as Fc receptor binding and augmented antigen-presenting function, the latter of which facilitates cytolytic T-cell activity.

The discovery that the immune system reacts to tumor cells has led to research into immune-based therapeutics for treating cancer. Antibody immunotherapies are already available, including monoclonal antibody products targeting specific tumor antigens (eg, bevacizumab targeting HER2/neu in breast cancer, rituximab targeting CD20 on B-cells in leukemia).²⁵ Since T-cells appear to play the most significant role in fighting cancer, they hold particular promise as an avenue of investigation for new cancer therapies. For this reason, in the upcoming chapters, we will take a closer look at T-cell functions, including how T-cells detect and target tumor cells, the mechanisms employed by tumor cells to evade these attacks, and the latest developments in T-cell—based immunotherapies.