Regression of Engineered Tumor Cells Secreting Cytokines Is Related to a Shift in Host Cytokine Profile from Type 2 to Type 1

Abstract

The precise role of the endogenous immune response in modulating cancer development remains unclear. In this study, three mouse tumor cell lines were used to elucidate the immune mechanisms for tumor regression versus tumor growth. These cell lines were (1) the poorly immunogenic V_KC_K cell line and (2) its two derived cell lines V_KC_K/RM4-tumor necrosis factor-alpha (TNF-alpha) and V_KC_K/RM4-interferon-gamma (IFN-gamma) engineered to secrete TNF-alpha and IFN-gamma, respectively. Our data showed that V_KC_K tumors grew aggressively in syngeneic BALB/c mice, and vaccination of irradiated V_KC_K cells failed to protect the mice from a subsequent challenge with the same tumor. In contrast, engineered V_KC_K tumor cells lost their tumorigenicity, and vaccination of engineered V_KC_K cells induced a protective immunity against V_KC_K cells that was mediated with V_KC_K-specific CD8⁺T cells. Susceptible mice developed a Th2-dominant response, whereas resistant mice developed a Th1-dominant response to V_KC_K. The T cell proliferative response and cytolytic activity against V_KC_K developed in both resistant and susceptible mice, but in the susceptible mice, these responses were much weaker compared with those in the resistant mice. Our results indicate that regression of tumor cells engineered to secrete cytokines TNF-alpha and IFN-gamma is related to a shift from a host type 2 to a type 1 cytokine profile. Our results further suggest that the failure of unmodified V_KC_K to generate efficacious T cells is not due to an inability to recognize tumor antigens but, rather, to the nature and magnitude of the antitumor immune response that develops. A better understanding of the mechanisms by which tumor cells modulate the host immune system may result in newer approaches for manipulating host-tumor interactions that favor the development of a protective antitumor immune response.