Is there such a thing as immunity to cancer

Recently, Markiewicz and Gajewski (1999) reviewed the history of immune surveillance beginning with the discoveries of the 1960s, through the disappointments of the 1980s and the new hopes of the 1990s. First, immunologists realized that cancers contain tumor specific antigens which are developmental and oncogenic markers. On occasion, tumors contained viral antigens. However, attempts in the 1980s to develop cancer vaccines or to upregulate the immune response with BCG or Interleukin-2 were singularly unsuccessful. These failures led many to doubt the existence of immune surveillance (Stutman, 1974, 1979; Klein and Boon, 1993) but, as experience with immunotherapy of cancer increased, it became clear that human neoplastic disease is much more complex than any mouse model. The evidence for protective immune involvement in cancer is summarized by the reviews cited in Table 12.1 below. To paraphrase Markiewicz and Gajewski, we now know that in humans: (i) immunosuppression increases the risk of cancer, particularly skin cancer; and, (ii) immune defects are often found in patients with cancer, above and beyond those predicted from the immunosuppressive effect of treatment with cytotoxic anti-cancer drugs.

Lastly, (iii) the most successful methods of immunization with tumor antigens and low molecular weight immunopotentiating agents have yielded positive clinical results in a significant number of patients with melanoma and renal cell carcinoma and some patients with adenocarcinoma of the breast. Thus, there is little doubt that immune surveillance does exist and plays a role in cancer immunity.

Table 12.1 Evidence in favor of immune surveillance.

Cancer incidence is increased in immunosuppressed individuals HIV Infection

Viral associated cancer Melanoma and lung cancer Recipients of organ transplants

Ultraviolet light and skin cancer

Cancer patients have depressed immune responsiveness

Escape from tumor immunity Skin cancer and suppressor T cells Alterations in T cell response

Immunological intervention benefits some cancer patients Melanoma and renal cell carcinoma Breast cancer

Brockmeyer and Barthel, 1998 Smith etal, 1998 Birkeland etal, 1995 Leigh etal, 1996 Schreiber, 1999 Strickland and Kripke, 1997

Pawelec etal., 1997 Strickland and Kripke, 1997 Pawelec etal., 1999 Markiewicz and Gajewski, 1999 Hadden, 1999

Pawelec etal., 1999 Hadden, 1999

UVB, the skin immune system and skin cancer

In addition to ultraviolet light's mutagenic effects, UVB promotes skin cancer by suppressing immune surveillance (reviewed by Strickland and Kripke, 1997). In laboratory animals, radiation at UVB wavelengths (280—320 nm) impairs the ability of the immune system to reject highly antigenic UV-induced skin cancers and respond to allergens and infectious organisms (van der Leun and Tevini, 1991; Kripke, 1984; Denkins etal, 1989; Jeevan etal, 1992). Additionally, subcarcinogenic doses of UV radiation contribute to the growth of skin cancers by generating antigen-specific suppressor T cells. These regulatory lymphocytes recognize UV-specific antigens on the tumors and prevent rejection of the tumor. Since their description in 1982 by Fisher and Kripke, this system of antigen-specific suppressor T cells, induced by UV radiation, has become the premier system for studying clinically-relevant immune suppression in cancer. Table 12.2 below summarizes two decades of progress in this area.

The induction of immune suppression by UV radiation can be broken down into the following discrete steps: (i) damage to keratinocytes; (ii) alteration of antigen presentation; (iii) induction of suppressor T cells; and, (iv) the effector function of suppressor T cells, directing the immune response away from induction and elicitation of delayed type hypersensitivity and cutaneous hypersensitivity. UV radiation directly and indirectly alters many of the immune mechanisms that recognize and control the growth of cutaneous neoplasms. Despite the many differences between mice and humans, findings in animal NMSC and melanoma models provide new insights into the immunobiology of human skin cancer and suggest new lines of investigation and new approaches to the prevention and immunotherapy of cutaneous malignancies.

Table 12.2 UV Radiation induces cells that suppress skin cancer immunosurveillance.

Investigators

Finding

Toews etal, 1980

Critical role of Langerhans cells in inducing downregulation.

Noonan etal., 1981

Suppression correlates with development of tumors.

Fisher and Kripke, 1982

First description of suppressor T cells in UV system.

Sauder etal, 1981

Epidermal cell are actively involved in suppression.

Elmets etal, 1983

Central role of T cells in suppression.

Schwarz etal., 1986

Cytokines are involved in inducing suppression.

Ullrich etal, 1986

Involvement of multiple pathways.

Okamoto and Kripke, 1987

Different pathways for effector and suppressor arms of response.

Cruz etal, 1989

Use of purified cell populations for induction of suppression.

Welsh and Kripke, 1990

Role of epidermal dendritic T cells.

Glass etal, 1990

Suppression is seen in all strains of mice.

Simon etal., 1991

Langerhans cell's function changes with UV treatment.

Simon etal., 1994

Th1 subpopulation of T cells is affected by UV.

Bucana etal, 1994

Ultrastructure of antigen presenting cells in UV suppression.

Muller etal, 1995

Alterations of antigen presenting cells.

Saijo etal, 1995

Antigen presenting function and suppressor cell induction

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