| Immune escape is an important reason why the immune system cannot control tumor growth, and many distinct mechanisms of immune evasion from natural, unmanipulated immune response have been identified. However, how immune resistance emerges during immunotherapy remains largely unexplored. Here, I describe a novel approach for studying tumor escape from immunotherapy. Through multiple rounds of in vivo selection, I derived a highly resistant cancer cell line (P3) from a susceptible cancer cell line (P0). Microarray analysis of P0 and P3 revealed that VCAM-1 is highly up-regulated in P3 resistant variant. Retroviral transfer of VCAM-1 into P0 significantly increased its resistance against a vaccine-induced immune response. This increase in immune resistance in vivo was associated with a reduction in the number of tumor-infiltrating CD8+ T cells and a near absence of apoptotic cells within the tumors expressing VCAM-1. Studies using mutated VCAM-1 show that this VCAM-1-induced immune resistance was mediated by its integrin receptor. Finally, surface staining of several human renal cell carcinoma cell lines showed that most human renal cell carcinoma have upregulated VCAM-1 expression. These data provided evidence that dysregulation of a cell adhesion molecule by a cancer can lead to immune evasion, and may have implications for treatment of human renal cell carcinoma using immunotherapy. |
