Resident research award: Tumor necrosis factor α selectively enhances growth and cytotoxic activity of tumor infiltrating lymphocytes from human colorectal cancer

Abstract

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL2) can induce regression of tumor metastases in animal models and in human metastatic malignant melanoma. We investigated the potential of colorectal cancer TIL as a source of killer cells and the effect of tumor necrosis factor α (TNFα) in combination with IL2 on their cytotoxic activity. Tumor-infiltrating lymphocytes were isolated from surgical specimens using a mechanical and enzymatic dissociation process. Autologous lamina propria mononuclear cells (LPMC) were used as control. Tumor-infiltrating lymphocytes and LPMC were cultured in the presence of IL2 with/without TNFα (1000 U/ml each) for 5 to 8 weeks. Cytotoxicity (% lysis) was tested against Daudi target cells in a 4-hr 51Cr-release assay. The combination of IL2 and TNFα resulted in a significantly greater-fold expansion of TIL than IL2 alone ( P < 0.01). Lamina propria mononuclear cells expanded less than TIL, and TNFα had an inhibitory effect on their growth ( P < 0.05). Tumor-infiltrating lymphocytes and LPMC showed comparable cytotoxicity when cultured with IL2 alone. However, the addition of TNFα augmented the killer activity of TIL while inhibiting that of LPMC ( P = 0.035). These results indicate that TNFα selectively increases the IL2-induced growth and cytotoxic function of colorectal cancer TIL, but not those of gut mucosal lymphoid cells, suggesting that TIL and LPMC differ in their response to TNFα. Therefore, this combination of cytokines may hold more promise than single agents for the immunotherapy of colorectal cancers with TIL.