Interactions between host immune cells and tumor cells within endogenous and cytokine modulated tumor microenvironments

Complex tumor microenvironments, of which hypoxia and cytokines are critical factors, can decrease the efficacy of various treatment modalities, including radiation and immunotherapy. The ability of hypoxia to alter tumor cell expression of adhesion receptors known to mediate immune cell trafficking into tissues was investigated. VCAM-1 was highly expressed on EMT6 mammary carcinoma cells under normal culture conditions, but was significantly reduced on hypoxic cells both in vitro and in vivo. ICAM-1 was not expressed on the surface of EMT6 cells at any oxygen concentration tested. These studies were extended using multi-gene arrays. All but 11 of the 536 genes analyzed were expressed at lower levels in EMT6 cells after 24 hrs of in vitro culture under hypoxic conditions than under normoxic conditions. The loss of adhesion molecule expression on hypoxic cells provides a possible mechanism for the previously observed retention of T lymphocytes within well-oxygenated regions of EMT6 tumors.; Cytokines can influence the molecular cascades that control tumor angiogenesis. Previous studies indicated that EMT6 tumors engineered to secrete IL-2 were less hypoxic, better vascularized, and more thoroughly infiltrated by tumor specific CTL than parental tumors. In the current work, IL-2-transfected tumors were found to be more sensitive to radiation therapy due to their reduced hypoxic fraction. These results support the combined use of radiation and immunotherapy in the treatment of cancer.; IL-12 exhibits potent anti-tumor activity in many experimental systems and certain human cancer therapies. EMT6 tumors and K1735 melanoma tumors engineered to secrete IL-12 were inhibited in their growth compared to parental tumors through distinct mechanisms. Mice bearing EMT6/IL-12 tumors produced specific CTL, which mediated the rejection of their tumors and provided lasting immunological protection. K1735/IL-12 tumors remained in a state of dormancy for several weeks through the inhibition of tumor angiogenesis. These mice failed to develop anti-tumor immunity and tumors began to grow as the cells lost their capacity to secrete IL-12.; These findings demonstrate the capacity of the tumor microenvironment to influence the interactions between tumor cells and immune cells. They also describe mechanisms by which cytokines can modulate these environments and improve cancer therapies.