Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape

Activated tumor-infiltrating lymphocytes may induce B7-H1 on melanocytes, which suggests adaptive resistance to antitumor immunity. The Great Escape In the movie The Great Escape, “problem” prisoners with multiple escape attempts are put in an “escape-proof” POW camp, where they use their cleverness and specialized skills to outwit their captors. However, when it comes to escaping, even Steve McQueen doesn’t have anything on cancer cells. Although human cancers express tumor antigens recognized by the immune system, host immune responses often fail to control tumor growth. Taube et al. now explain one way in which tumor cells may adapt to escape from immune surveillance. The researchers found a strong association between expression of the immune-inhibitory molecule B7-H1 (PD-L1) on melanocytes and immune cell infiltration into tumors in patients with different stages of melanoma. The B7-H1+ melanocytes were found directly adjacent to the immune cells, with interferon-γ detected at the melanocyte–immune cell interface. Interferon-γ, which is secreted by the immune cells, induces B7-H1 expression; thus, the tumor may adapt by causing immune cells to trigger their own inhibition. Indeed, patients with B7-H1+ metastatic melanoma had prolonged overall survival when compared with B7-H1− metastatic melanoma patients, perhaps suggesting that B7-H1 expression by the tumors is stimulated by a more successful immune response. It remains to be seen whether blocking B7-H1 in these patients will further improve survival. But it is clear that for both prisoners and tumors, adaptation is the key to escape. Although many human cancers such as melanoma express tumor antigens recognized by T cells, host immune responses often fail to control tumor growth for as yet unexplained reasons. Here, we found a strong association between melanocyte expression of B7-H1 (PD-L1), an immune-inhibitory molecule, and the presence of tumor-infiltrating lymphocytes (TILs) in human melanocytic lesions: 98% of B7-H1+ tumors were associated with TILs compared with only 28% of B7-H1− tumors. Indeed, B7-H1+ melanocytes were almost always localized immediately adjacent to TILs. B7-H1/TIL colocalization was identified not only in melanomas but also in inflamed benign nevi, indicating that B7-H1 expression may represent a host response to tissue inflammation. Interferon-γ, a primary inducer of B7-H1 expression, was detected at the interface of B7-H1+ tumors and TILs, whereas none was found in B7-H1− tumors. Therefore, TILs may actually trigger their own inhibition by secreting cytokines that drive tumor B7-H1 expression. Consistent with this hypothesis, overall survival of patients with B7-H1+ metastatic melanoma was significantly prolonged compared with that of patients with B7-H1− metastatic melanoma. Therefore, induction of the B7-H1/PD-1 pathway may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity and may explain how melanomas escape immune destruction despite endogenous antitumor immune responses. These observations suggest that therapies that block this pathway may benefit patients with B7-H1+ tumors.