GENETICS & DISEASE
Cancer biology Bringing battlers to the tumor
Chemotherapeutic drugs fight melanoma by attracting immune cells into tumors
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 che- mokines1
. 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 endog- enous 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 chemo-
therapeutic drugs commonly used to treat advanced human melanoma could induce chemokine expression in the tumors. When they treated human melanoma cell lines with three che- motherapy drugs, they observed increased secretion of chemo- kines 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 chemo- kines in tumors before and after chemotherapy. They found
48
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.
■
1. Hong, M. et al. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Research 71, 6997 (2011)
A*STAR RESEARCH OCTOBER 2011– MARCH 2012
©
iStockphoto.com/jcarillet
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96