"This research establishes that macrophages can cause disease as opposed to current dogma which asserts that the purpose of these cells is benevolent, solely to assist in fighting disease," said the study's lead investigator, Michael S. McGrath, MD, PhD, UCSF professor of laboratory medicine at UCSF's Positive Health Program at San Francisco General Hospital Medical Center (SFGHMC). The study is published in the October issue of Cancer Research.
Researchers used SCID (severe combined immunodeficiency disease) mice that lack functional T and B lymphocytes and are used for the study of human lymphoid tissues. They injected mice with tumor cells--some with macrophages and lymphoma cells together, some with macrophages separately, and some with lymphoma cells separately--from HIV-infected patients with a rare form of non-Hodgkin's lymphoma. They also injected some mice with normal human macrophages from healthy subjects.
"Most scientists believe that the macrophages present in tumors are there to help fight the cancer," said McGrath.
The mice injected with both macrophages and lymphoma cells from the HIV-infected lymphoma patients and mice injected with only the macrophages (separated from the lymphoma cells) from the HIV-infected lymphoma patients developed lymphomas.
None of the mice injected with just the lymphoma T-cells from the HIV-infected lymphoma patients and none of the mice injected with normal human macrophages from healthy subjects developed lymphomas.
"Our theory is that, during HIV infection, disease associated macrophages have HIV inserted near growth promoting genes allowing macrophages to become neoplastic. These cells begin to proliferate, another event that classical thinking about macrophages says is impossible. In addition, these proliferating macrophages, "pro macs", do what all macrophages do and produce factors. Normal macrophages produce factors--which can be any number of substances--to help fight diseases. Pro macs, instead, produce factors that stimulate lymphoma growth," said McGrath.
In addition, these HIV-infected macrophages are an important reservoir of HIV infection that remains unaffected by current antiretroviral therapies, McGrath said. New therapies targeting HIV-infected macrophages hold promise not only for fighting lymphoma, but also could assist in eliminating latent reservoirs of HIV.
A phase I/II clinical trial testing one of these therapies (SL11047) recently opened at UCSF under the direction of Lawrence D. Kaplan, MD, UCSF professor of clinical medicine and director of the UCSF Lymphoma Program. This trial specifically targets individuals with relapsed HIV-associated lymphomas. A second trial for patients with other (non-HIV) lymphomas is expected to open before the end of this year.
Co-investigators are Elisabeth Zenger, DVM, PhD, associate specialist at UCSF; Nancy W. Abbey, staff research associate at UCSF's department of anatomic pathology at SFGHMC; Mark D. Weinstein, BS, staff research associate at UCSF's department of pathology at SFGHMC; Leon Kapp, PhD, senior scientist, and Jeremy Reis, research technician, at SLIL Biomedical Corporation; Inessa Gofman, technician at the school of medicine at UC Davis; Lt. Commander Carl Millward, MD, staff pathologist in the department of soft tissue pathology at the Armed Forces Institute of Pathology, Washington, D.C.; Ron Gascon, UCSF staff research associate at SFGHMC; and Brian G. Herndier, MD, PhD, UCSD professor of clinical pathology in UCSD's pathology department.
The research was funded by the National Institutes of Health and SLIL Biomedical Corporation. Specimens were obtained from the AIDS and Cancer Specimen Resource.
Journal
Cancer Research