Phenotypic and functional analyses of tumor-infiltrating lymphocytes (TILs) used in clinical trials revealed that cells other than CTLs can have antitumor efficacy. This observation led us to search for mechanisms for
tumor recognition by lymphocytes that utilize alternatives to surface structures of
tumor cells, for example, MHC
antigen complexes; the latter are generally believed to be the immunogenic platforms for CTLs. Therefore, as a possible source of immunostimulatory activity, we compared the ability of plasma membrane components of tumor cell lines with first secreted
tumor cell components and then intracellular
tumor components to act as mitogenic sources for human TIL lines. Surprisingly, the latter was found to be most potent, particularly Oncoimmunin-L, which is a 45-kDa
protein with sequence similarity to members of the
serpin family of
proteins. This
protein, which has at least a 31% sequence identity to
human leukocyte elastase inhibitor and stimulates [3H]-
thymidine incorporation into the
DNA of human TILs, may be found in the cytosol of many
tumor cells. Taken together with our earlier work in which a 36-kDa
protein, also of
tumor cytosolic origin, was shown to induce differentiation of myeloid cells, we propose soluble factors derived from
tumor cells as a pathophysiological source of
tumor immunogenicity. Moreover, detailed biochemical and biophysical characterization of
tumor cell-immunocyte interactions will define the
tumor immunoenvironment.