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Host Response to Tumors

By Dmitry Gabrilovich, MD, PhD, Christopher M. Davis Professor in Cancer Research, Program Leader, Translational Tumor Immunology; Professor, The Wistar Institute; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania

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The immune response to foreign antigens consists of

  • Humoral mechanisms (eg, antibodies)

  • Cellular mechanisms

Most humoral responses cannot prevent tumor growth. However, effector cells, such as T cells, macrophages, and natural killer cells, have relatively effective tumoricidal abilities. Effector cell activity is induced by cells that present tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) on their surface (these cells are called antigen-presenting cells) and is supported by cytokines (eg, interleukins, interferons). Despite the activity of effector cells, host immunoreactivity may fail to control tumor occurrence and growth.

Cellular Immunity

The T cell is the primary cell responsible for direct recognition and killing of tumor cells. T cells carry out immunologic surveillance, then proliferate and destroy newly transformed tumor cells after recognizing TAAs. The T-cell response to tumors is modulated by other cells of the immune system; some cells require the presence of humoral antibodies directed against the tumor cells (antibody-dependent cellular cytotoxicity) to initiate the interactions that lead to the death of tumor cells. In contrast, suppressor T cells inhibit the immune response against tumors.

Cytotoxic T lymphocytes (CTLs) recognize antigens on target cells and lyse these cells. These antigens may be cell surface proteins or may be intracellular proteins (eg, TAAs) that are expressed on the surface in combination with class I major histocompatibility complex (MHC) molecules. Tumor-specific CTLs have been found in

Natural killer (NK) cells are another population of effector cells with tumoricidal activity. In contrast to CTLs, NK cells lack the receptor for antigen detection but can still recognize normal cells infected with viruses or tumor cells. Their tumoricidal activity is termed natural because it is not induced by a specific antigen. The mechanism by which NK cells discriminate between normal and abnormal cells is under study. Evidence suggests that class I MHC molecules on the surface of normal cells inhibit NK cells and prevent lysis. Thus, the decreased level of class I molecule expression characteristic of many tumor cells may allow activation of NK cells and subsequent tumor lysis.

Macrophages can kill specific tumor cells when activated by a combination of factors, including lymphokines (soluble factors produced by T cells) and interferon. They are less effective than T-cell–mediated cytotoxic mechanisms. Under certain circumstances, macrophages may present TAAs to T cells and stimulate tumor-specific immune response. There are at least 2 classes of tumor-associated macrophages (TAM):

  • TAM-1 (M1) cells facilitate T cell killing of tumors

  • TAM-2 (M2) cells promote tumor tolerance

Recently this classification was revisited. Currently M1 and M2 are considered to exist on a continuum until they maximally differentiate (polarize) into M1 and M2. Such polarization can vary over time and depends on the stage and type of cancer as well as treatments.

Dendritic cells are dedicated antigen-presenting cells present in barrier tissues (eg, skin, lymph nodes). They play a central role in initiation of tumor-specific immune response. These cells take up tumor-associated proteins, process them, and present TAAs to T cells to stimulate the CTL response against tumor. Several classes of dendritic cells can mediate tumor promotion or suppression.

Lymphokines produced by immune cells stimulate growth or induce activities of other immune cells. Such lymphokines include interleukin-2 (IL-2), also known as T-cell growth factor, and the interferons. IL-12 is produced by dendritic cells and specifically induces CTLs, thereby enhancing antitumor immune responses.

Regulatory T cells are normally present in the body and help prevent autoimmune reactions. They are produced during the active phase of immune responses to pathogens and limit the strong immune response that could damage the host. Accumulation of these cells in cancers inhibits antitumor immune responses.

Myeloid-derived suppressor cells consist of immature myeloid cells and their precursors. These cells increase in number in cancer as well as inflammation and infection. The cells have potent immune suppressive activity. Two populations of these cells are recognized:

  • Granulocytic

  • Monocytic

Myeloid-derived suppressor cells accumulate in large numbers in cancers and predict poor clinical outcomes in various types of cancer.

Humoral Immunity

In contrast to T-cell cytotoxic immunity, humoral antibodies do not appear to confer significant protection against tumor growth. Most antibodies cannot recognize TAAs. Regardless, humoral antibodies that react with tumor cells in vitro have been detected in the sera of patients with various tumors, including

Cytotoxic antibodies are directed against surface antigens of tumor cells. These antibodies can exert anti-tumor effects through complement fixation or by serving as a flag for destruction of tumor cells by T cells (antibody-dependent cell-mediated cytotoxicity). Another population of humoral antibodies, called enhancing antibodies (blocking antibodies), may actually favor rather than inhibit tumor growth. The mechanisms and relative importance of such immunologic enhancement are not well understood.

Failure of Host Defenses

Although many tumors are eliminated by the immune system (and thus are never detected), others continue to grow despite the presence of TAAs. Several mechanisms have been proposed to explain this deficient host response to the TAA, including the following:

  • Specific immunologic tolerance to TAAs in a process that involves antigen-presenting cells and suppressor T cells, possibly secondary to prenatal exposure to the antigen

  • Suppression of immune response by chemical, physical, or viral agents (eg, helper T-cell destruction by HIV)

  • Suppression of the immune response by cytotoxic drugs or radiation

  • Suppression of the immune response by the tumor itself through various complex and largely uncharacterized mechanisms that cause various problems including decreased T, B, and antigen-presenting cell function, decreased IL-2 production, and increased circulating soluble IL-2 receptors (which bind and hence inactivate IL-2)

  • Presence and activity of TAM-2 (M2) polarized cells, promoting tumor tolerance