A drug first designed to prevent cancer cells from multiplying has a second effect: it switches immune cells that turn down the body鈥檚 attack on tumors back into the kind that amplify it. This is the finding of a study led by researchers from 嘿嘿视频 Medical Center and in Cancer Immunology Research.
According to experiments in mice, macrophages鈥攊mmune cells that home in on tumors鈥攖ake in the drug nab-paclitaxel (brand name Abraxane庐). Once inside these cells, say the study authors, the drug changes them so that they signal for an aggressive anti-tumor immune response.
鈥淥ur study reveals a previously unappreciated role for Abraxane庐 in tumor immunology,鈥 says corresponding author , Senior Vice President and Vice Dean for Science, Chief Scientific Officer at 嘿嘿视频.
鈥淚n doing so, it suggests ways to improve the drug and argues for its inclusion in new kinds of combination treatments,鈥 says Dr. Bar-Sagi, also a professor in the at 嘿嘿视频, and associated with its Perlmutter Cancer Center.
Nab-paclitaxel over Paclitaxel
Abraxane庐 is comprised of the decades-old cancer drug, paclitaxel, combined with nanoparticles of the protein albumin (nab). Paclitaxel alone is not effective against pancreatic cancer, but Abraxane庐 is part of a leading treatment for the disease. Why the albumin-bound form works better has been a major question in the field.
Paclitaxel prevents structures called microtubules inside cancer cells from breaking up, a required step if they are to multiply as part of abnormal growth. Many in the field assume that nab-paclitaxel too primarily targets microtubules in cancer cells, with albumin perhaps helping the drug to get inside cells, and with fewer toxic side effects.
The new findings suggest that, on top of any effect on cancer cells, the effectiveness of Abraxane庐 may proceed from its impact on macrophages, which roam the bloodstream and build up in many tumors.
The study results revolve around the immune system, in which cells like macrophages trigger a massive attack on bacteria or other invading microbes. This system can also recognize and attack cancer cells. Factors secreted by tumor cells, however, dampen the immune response in part by switching macrophages from their immune-stimulating stance, termed M1, into an M2 mode that suppresses their immune function.
In experiments in macrophage cell lines, the study authors found that nab-paclitaxel is more effective than paclitaxel partly because albumin enables macrophages to take up the drug through a natural process called macropinocytosis.
Once inside macrophages, according to experiments in mice with pancreatic tumors, nab-paclitaxel causes the macrophages to switch from immune-suppressing M2 cells back into M1 cells that amplify the body鈥檚 effort to kill cancer cells. Past studies had found that paclitaxel has a similar structure to substances given off by bacteria that trigger macrophage activation. The study authors show that the same pathway is evoked by nab-paclitaxel in pancreatic tumor-associated macrophages.
鈥淥ur findings argue that it may be possible to develop more treatments that selectively target macrophages by coupling albumin to immune-activating agents,鈥 says聽lead study author Jane Cullis, PhD, a postdoctoral fellow in Dr. Bar-Sagi鈥檚 lab. 鈥淲e may also be able to adjust albumin鈥檚 structure such that drugs attached to it stay in macrophages longer, or combine Abraxane庐 with T-cell treatments for greater therapeutic effect. In principle, such treatments should be useful against the many tumor types infiltrated by macrophages.鈥
Along with Dr. Cullis and Dr. Bar-Sagi, authors of the study were Despina Siolas and Antonina Avanzi in the Department of Biochemistry and Molecular Pharmacology at 嘿嘿视频; and Sugata Barui and Anirban Maitra in the departments of Pathology and Translational Molecular Pathology at University of Texas MD Anderson Cancer Center. The work was supported by a grant from the American Association for Cancer Research (AACR PanCAN 13-90-25-VOND), the National Institutes of Health (5-T32 CA 009161-39, 5-T32AI100853-04, and HL007151-36), and a Schwartz Fellowship.
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