Intratumor Immunologic Heterogeneity

Tumor cells express a great variety of antigens including tumor specific transplantation antigens, tumor-associated antigens, differentiation antigens, histocompatibility antigens, lectin-binding sites and receptors for natural killer cells and natural antibodies. These antigens are distributed unevenly on tumor subpopulations and each subpopulation may induce different immune responses to the same determinant. Intratumor immunologic heterogeneity arises early in cancer, possibly during preneoplasia, and exists throughout the course of progression. Metastatic subpopulations are not generally less antigenic than subpopulations within primary tumors. Different arrays of antigenic determinants are displayed by subpopulations but variability in cell surface expression of a single determinant is also a fundamental type of immunologic heterogeneity. Antigenic specificity patterns commonly reveal one-way cross-reactions between tumor subpopulations. One-way cross-reactions might occur due to quantitative differences, cell-cycle variations, modulation, masking, H-2 expression and restriction phenomena, or alteration in the carbohydrate side-chains of glycoproteins. Interactions which occur when subpopulations co-exist may alter immune responses so that the response to the mixture is not the sum of the responses to the individual subpopulations. It is suggested that the exploitation of the mechanisms involved in immunologic heterogeneity may lead to new therapeutic approaches and that the great diversity of determinants expressed by tumor cells could lead to development of multivalent panel of monoclonal antisera which, acting synergistically, could preferentially lyse tumor cells.