Immunology of the Lymphomas

Abstract

In the past 50 years, important discoveries have helped our current understanding of the immune system and its neoplasms. Early investigations led to the identification of distinct subpopulations of lymphocytes, the T (thymic-derived), B (bursa-equivalent), and natural killer (NK) lymphocytes that were not necessarily discernible by morphology and had differing functions (Papermaster and Good, Nature, 196:838–840, 1962 and Cooper et al., Nature 205:143–146, 1965). Cell-mediated immunity was found to be a function of T lymphocytes, while antibody responses (humoral immunity) were found to be a function of B lymphocytes. T and B cells were differentiated by the presence of certain antigens or proteins on their cell surfaces, specifically erythrocyte-rosette receptors (T) and surface immunoglobulins (B). It was later noted that different stages of lymphocyte maturation could be distinguished by the combination of particular antigens, generally glycoproteins, present on the cell surface, termed differentiation antigens. These antigens may be identified by specific, pure hybridoma antibodies (monoclonal antibodies) raised against them. The discovery of surface antigens on lymphocytes revolutionized the study of lymphoma (Nowell, Cancer Res, 20:462–466, 1960; Shevach et al. Transplant Rev, 16:3–28, 1973; and Jaffe et al., Cancer Treat Rep, 61:953–962, 1977). The combination of surface antigens (now termed cluster designation or CD group) present on a particular cell was designated its immunophenotype. The use of immunophenotypes has been helpful in classifying lymphomas into groups of B- or T-cell types and has provided insight into lymphocyte maturation. The result has been the development of new schemas of lymphocyte differentiation and new histologic classification systems attempting to correlate histology with phenotype. The progress in technology at the molecular level now permits detection of the earliest commitment to B- and T-lymphoid differentiation and serves to confirm immunophenotypic data. These technological advances have also led to the development of novel, targeted therapeutics in the form of monoclonal antibodies specific for the malignant equivalent of the developmental antigens associated with differentiation. As our understanding of immunologic interactions and function has matured, it has also become possible to modify these functions that may prevent tumor cell apoptosis and augment tumor cell killing by T and NK cells. Most recently, immune checkpoint inhibitors active in lymphoma have also been developed and are now becoming standard of care in treating a variety of lymphoid tumors. As described below, our ability to harness the immune system has progressed from developing a single “magic bullet” to amassing an arsenal of weaponry in the treatment of lymphoma.