Primary chemically induced tumors induce profound immunosuppression concomitant with apoptosis and alterations in signal transduction in T cells and NK cells

Whereas transplantable tumors can be readily cured with immunotherapeutic a pproaches, similar therapies in cancer patients have been less effective. T his difference may be explained by an immunosuppression resulting from the presence of a slowly growing primary tumor in the patient, whereas the immu ne system in a mouse with a rapidly proliferating transplantable tumor woul d be less affected. As a more appropriate model to the immune dysfunction i n patients, slowly progressing primary tumors were induced by the carcinoge n methylcholanthrene (MC) in mice, Their ability to induce immunosuppressio n in T cells and natural killer (NK) cells was compared to that of rapidly growing transplanted MC-induced tumors. The results demonstrate that mice b earing primary MC tumors had significantly diminished T-cell and NK-cell fu nctions, impaired capacity to produce Th1 cytokines, and markedly reduced l evels of the signal-transducing zeta chain in T cells and NK cells, similar to that described in cancer patients. Moreover, a substantial number of CD S' T cells in mice with large primary MC tumors were undergoing apoptosis, correlating with alterations in CD4/CD8 ratios. In contrast, T cells and NK cells from mice bearing rapidly growing transplanted tumors were only marg inally affected. These findings could explain the apparent discrepancy betw een the consistent findings of a diminished immune response and alterations in signal transduction in cancer patients as compared to the less reproduc ible observations in murine transplantable tumors. In addition, they could explain the differences in the high efficacy of immunotherapy in mice with transplantable tumors and the low therapeutic results in cancer patients.