Anti-tumor potential of type-I NKT cells against CD1d-positive and CD1d-negative tumors in humans

Vα24-invariant natural killer T cells (NKTs) are strictly CD1d-restricted, and CD1d expression has been found in several types of leukemia and lymphoma as well as in brain tumors suggesting that these malignancies could be targeted for direct NKT-cell cytotoxicity. Several studies have revealed strong positive associations between the numbers of tumor-infiltrating or circulating NKTs with improved disease outcome in patients with diverse types of CD1d-negative solid tumors. The mechanism by which NKTs mediate anti-tumor activity against CD1d-negative tumors has long remained enigmatic. Recent evidence indicates that NKTs can suppress tumor growth indirectly by targeting CD1d-positive elements of tumor-supportive stroma such as tumor-associated macrophages. This review summarizes the current knowledge about the mechanisms that regulate NKT-cell localization to the tumor site and their interaction with the tumor microenvironment. The discussed strategies for pharmacologic modulation and genetic engineering of NKTs may lead to development of effective and broadly applicable immunotherapies of cancer.