Human tumor-infiltrating lymphocytes: a marker of host response.

Abstract

There is continuing interest in the possibility of immunologic intervention in the therapy of malignant disease. By employing a range of different techniques, it has been possible to show the presence of activated helper, suppressor, and cytotoxic T cells, B cells, NK precursors, and macrophages at the tumor site. The overwhelming impression from our data is that tumors may be subject to immunologic attack by heterogeneous effectors and that there is selective trapping of these effectors with corresponding depletion at the periphery. Like all inflammatory sites, however, the tumor contains both positive and negative regulatory mechanisms with the coexistence of cells with effector and suppressor functions, eg, T suppressors that modulate the proliferative response of T helpers and macrophages suppressing NK function contribute to the dynamic interplay in situ. Additional complexity is indicated by immunohistologic studies that clearly show that the stroma rather than foci of tumor cells are the site of infiltration, thereby further limiting effector function. We are now at the end of the descriptive stage of our investigations and further studies must approach the more difficult problem of modifying the host response in such a way as to alter the balance between effector and suppressor activity. A promising area of research would appear to be the use of cloned helper T cells or their products in the immunotherapy of cancer. The demonstration, by us, of selective trapping at tumor sites suggests that administration of the patients' own T cells with antitumor reactivity may serve as an efficient delivery vehicle to activate host effectors in situ. Studies in animal systems have shown the feasibility of this approach, although the failure of cultured T cells to undergo normal recirculation represents a considerable unresolved problem. Effector function by each of the tumor-infiltrating cell types described is under T cell control, and preliminary studies have already indicated the ability of helper T cells to accelerate allograft and tumor rejection. The increasing availability of gene-cloned materials with potent biologic activity opens new areas of research in cancer therapy. The lymphokines IL-2 and interferon are already undergoing clinical trials. Studies by Hersey demonstrate that administration of conditioned medium containing impure IL-2 results in the appearance of antitumor effectors in previously nonreactive melanoma patients, and Rosenberg, among others, has shown IL-2 to be a potent enhancer of alloimmune responses. Lymphokine-activating macrophages also augment antitumour responses.(ABSTRACT TRUNCATED AT 400 WORDS)