The importance of lymphoid cells in tumor immunity has been repeatedly shown in animal experiments. The T cell is the primary cell thought to be responsible for direct recognition and killing of tumor cells. T cells carry out an immunologic surveillance, destroying newly transformed tumor cells after recognizing TAAs. In humans, specific T-cell clones can be grown, which recognize and directly kill autologous tumor cells. T cells are uniquely capable of killing cells expressing TAA intracellularly because peptide fragments derived from these intracellular proteins can be bound to class I MHC antigens on the tumor cell surface, which can be recognized by cell-surface T-cell receptors. Thus, antigens recognized by cytotoxic T-lymphocytes (CTLs) do not have to be cell-surface proteins, but can be intracellular or even intranuclear proteins. These molecules may represent ideal immunotherapeutic targets because they may be directly involved in the dysregulation of cell growth associated with cancer development.
Tumor-specific CTLs have been found with neuroblastomas, malignant melanomas, sarcomas, and carcinomas of the colon, breast, cervix, endometrium, ovary, testis, nasopharynx, and kidney. The significance of immune reactions in controlling tumor growth is not clear, but it seems likely that T cells can damage tumor cells in vivo under some conditions. Natural killer (NK) cells, which can kill tumor cells, are also found in persons without tumors. NK cells appear to recognize certain common features of tumor cells, particularly low levels of class I MHC molecules. Some T 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.
Although apparently less effective than T-cell-mediated cytotoxic mechanisms, macrophages can kill specific tumor cells when activated in the presence of TAAs, lymphokines (soluble factors) produced by T cells, or interferon (IFN). Other T cells, termed suppressor T cells, inhibit the production of an immune response against tumors. The antigen-presenting cell is also key in immune response induction. This cell is present in barrier tissues (eg, skin, lymph nodes) and presents new antigens to immune effector cells, such as T cells.
In addition to diverse cell populations, 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. Recently described growth factors, such as interleukin-12 (IL-12), specifically induce CTLs rather than suppress T-cell responses and thus enhance antitumor immune responses.
Humoral antibodies that react with tumor cells in vitro are produced in response to various animal tumors induced by chemical carcinogens or viruses. Humoral antibodies directed against human tumor cells or their constituents have been shown in vitro in the sera of patients with Burkitt’s lymphoma, malignant melanoma, osteosarcoma, neuroblastoma, and lung, breast, and GI carcinomas. However, humoral antibody-mediated protection against tumor growth in vivo is demonstrable only in certain animal leukemias and lymphomas. In contrast, lymphoid cell-mediated protection in vivo occurs with many animal tumors.
Cytotoxic antibodies are complement-fixing in general and are directed against surface antigens of relatively high density. IgM antibodies usually are more cytotoxic in transplantation systems than are IgG antibodies.
Enhancing antibodies (blocking antibodies) may favor rather than inhibit tumor growth. They generally are IgG, possibly complexed with soluble antigen. The mechanisms and relative importance of such immunologic enhancement are not well understood but may involve soluble immune complexes and suppressor T cells. The relationship of cytotoxic and enhancing antibodies is not clear; ie, whether these antibodies are distinct from each other is unknown.
Alterations of Host Immunoreactivity
Tumors with TAAs can grow in vivo, which suggests a deficient host response to the TAA. Possible mechanisms are as follows: (1) Specific immunologic tolerance to TAA may develop (eg, because of prenatal exposure to the antigen, possibly viral in origin). This may involve suppressor T cells in some manner. (2) Chemical, physical, or viral agents may suppress the immune response. A dramatic example of the latter occurs in patients with HIV infection, in which helper T cells are selectively destroyed by the virus. (3) Therapy, especially cytotoxic drugs and radiation, may suppress the immune response. Patients undergoing immunosuppressive therapy for renal transplantation have an incidence of tumors > 100 times that expected, suggesting an impairment of the postulated immune surveillance mechanisms. Such tumors are generally lymphoid malignancies rather than commonly prevalent cancers (eg, lung, breast, colon, prostate).
Tumors that have been inadvertently transplanted to human kidney recipients undergoing immunosuppressive therapy regress when immunosuppression is discontinued. In contrast to this detrimental effect of immunosuppressive drugs or radiotherapy, pretreatment of cancer patients with low-dose cyclophosphamide inhibits suppressor T-cell responses to tumor cell vaccines and other antigens, thereby potentially enhancing tumor immunity. (4) The tumor itself may suppress the immune response. Deficient cellular immunity can be associated with recurrence and dissemination of tumors, although cause and effect are difficult to distinguish. This deficiency has been repeatedly shown in various tumors, most dramatically in Hodgkin’s disease, which appears to involve a variable defect in T-cell function.
Decreased IL-2 production, an increase in circulating soluble IL-2 receptors, and induced defects in antigen-presenting cell function may also be involved. Defective function of the T cells infiltrating the tumor has been shown and can be overcome by sufficient antigen presentation by antigen-presenting cells and appropriate cytokine support. Deficient humoral immunity is commonly associated with neoplasms involving abnormal B-cell derivatives (eg, multiple myeloma, chronic lymphocytic leukemia).
Revision date: June 14, 2011
Last revised: by Jorge P. Ribeiro, MD