Chemotherapy has long been the mainstay of treatment for advanced melanoma — the most life-threatening form of skin tumor. Jean-Pierre Abastado at the A*STAR Singapore Immunology Network and co-workers have now demonstrated that chemotherapy could drive melanoma cells to express chemokines. These chemokines would then lure immune cells to attack melanoma cells, thereby promoting tumor regression and enhancing patient survival.
Previous studies have linked immune cell invasion to patient survival in different types of cancer, but the researchers wondered why some tumors recruited more immune cells than others. They studied mice that had spontaneously developed endogenous skin tumors, and found few immune cells within the tumors. However, when they transplanted melanoma cells into mice, they found that immune cells did invade the tumors. The result suggests that there was something different about each of the tumor environments that led to differential abilities to recruit immune cells.
Chemokines are proteins that can induce the infiltration of immune cells. The researchers found that endogenous tumors expressed much lower levels of various chemokines, including CXCL9, than tumors derived from the transplanted cell lines. When they induced the expression of CXCL9 in the endogenous tumors, the tumors were able to recruit more immune cells, and the tumor cells were more likely to die than in tumors that did not express high levels of CXCL9.
Abastado and his team then investigated whether chemotherapeutic drugs commonly used to treat advanced human melanoma could induce chemokine expression in the tumors. When they treated human melanoma cell lines with three chemotherapy drugs, they observed increased secretion of chemokines by the cancer cells. When mice with tumors were treated with chemotherapy, the researchers also observed an increase in tumor expression of chemokines, which led to enhanced immune cell invasion into the tumors.
The researchers subsequently studied human patients with advanced melanoma and examined the expression of chemokines in tumors before and after chemotherapy. They found that chemotherapy increased the expression of chemokines in tumors that seemed to respond to the drugs, but not in tumors that continued to grow and therefore did not respond. The melanoma patients that demonstrated higher chemokine levels after chemotherapy survived longer than those with lower levels.
As melanomas respond to chemotherapeutic drugs in only 10% of patients, the findings could aid the future development of improved chemotherapies. “We are now screening for new drugs able to attract immune cells even more vigorously than existing drugs,” says Abastado.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network.