Unique Immunoregulation of Lung Cancer by CD8+ T Cells

Abstract

Abstract We hypothesize that immunoregulation of lung cancer differs from that of other malignancies. To study this hypothesis in greater detail, we utilized a primary carcinogenesis model of 3-MCA-induced flank fibrosarcoma or urethane-mediated lung cancer in B6 wild-type or CD8+ T cell deficient mice. CD8+ T cell deficiency increased sarcoma tumor growth (199±65 vs. 511±138 mm 3for B6 vs B6 CD8−/−mice respectively p = 0.03) but decreased the growth of lung cancer (1.7±0.2 vs. 0.6±0.13 cm 3for B6 vs B6 CD8−/−mice respectively p = 0.006). We validated this surprising finding in multiple other tumor models including B16 melanoma, EG7 lymphoma and LLC lung cancer. For all non-lung cancer tumors, the presence of CD8+ T cells decreased tumor growth. In direct contrast, the presence of CD8+ T cells accelerated the growth of lung cancer. Cytokine analysis revealed a significant CD8+ T cell-dependent increase of Th-1 polarizing cytokines, IFN-γ and TNF-α, in LLC lung cancer-bearing but not B16 melanoma-bearing mice. Similar to CD8+ T cell deficiency, neutralization of IFN-γ and TNF-α in B16 melanoma-bearing mice increased tumor growth but ameliorated the growth of lung cancer. In addition, we noted an IFN-γ and TNF-α-dependent expansion of CD8+Foxp3+ T cells in the tumor infiltrating lymphocytes of lung cancer-bearing mice, but not melanoma-bearing mice. Therefore, contrary to the accepted dogma, an increase in Th-1 polarizing cytokines, mediated in some fashion by lung cancer associated CD8+ T cells, facilitates rather than ameliorates the growth of this malignancy. Our data suggests that immunoregulation of lung cancer is unique and may require novel immunomodulating strategies that may not necessarily apply to other malignancies. This project was funded by P01 AI116501, R01 AI145108, I01BX002299