- A new pathway of
the immune response against cancer is identified by a research team from
NYU Langone Medical Centre.
- Macrophages are
switched from being M2 cells into M1 cells, resulting in a strong immune
activation could be used in drug therapy against different types of
research team from NYU Langone Medical Center has found that a drug which was
designed to block the multiplication of cancer cells could also switch certain
immune cells from lowering the body's attack on tumors into the kind that leads
to amplification of immune response. The study was published in the journal
Cancer Immunology Research
and highlighted aspects of the drug
nab-paclitaxel that were so far unknown.
The experiments were carried out on mice
and the drug nab-paclitaxel, with a brand name Abraxane (protein-bound
paclitaxel), entered the macrophages and altered them into mounting an
aggressive tumor response. Dr. Dafna Bar-Sagi who is the Vice Dean for Science
and Chief Scientific Officer at NYU Langone said that the study unearthed a
role of Abraxane that was not associated with it till now. She further stated
that these findings could be used to improve the drug and to include the drug
in new combinations.
‘New pathway of macrophage activation by abraxane (protein-bound paclitaxel) can be used to enhance therapy against cancer.’
is a drug used for cancer for over
many decades and Abraxane is a combination of this cancer drug with nano
particles of the protein albumin (nab). Paclitaxel is not found to be effective
in the treatment of pancreatic cancer when it is used alone but Abraxane is a
leading method of treatment of the disease condition. There have been many
questions raised among the scientific community about how the drug that consists
of the albumin is more effective in treatment.
Mode of Action of
cells break-up microtubules inside the cells that aid in their multiplication.
Paclitaxel does not allow these microtubules from breaking up which arrests
Mode of Action of
nab-paclitaxel are also believed to primarily target the break-up of
microtubules in cancer cells, with albumin aiding the drug in getting into the
cells, resulting in lower toxic side-effects.
from its effect on cancer cells, Abraxane also exerts its influence on
macrophages that are present in large numbers in the blood stream. Macrophages
are known to mount a strong immune reaction against invading bacteria and other
microbes. These cells also recognize cancer cells and can mount an immune
response. However, certain factors secreted by cancer cells are found to switch
off these macrophages, from M1 cells into M2 cells, and prevent them from
attacking the cancer cells.
Macrophages in Tumor
are referred to as Type I(M1) or Type II(M2) cells based on their activation
state. The difference between the two types of macrophages is due to the
difference in expression of receptors, production of cytokine and the variation
in function between the two cells.
cells: Studies have shown that Type I macrophages (M1) can
- Produce high
level of proinflammatory cytokines
- Express large
amount of Major Histocompatibility Complex (MHC) molecules
- Associated with
the killing of pathogens and of tumor cells.
- The M1
macrophages lead to an antitumor response by secreting the factors TNF-α,
cells: These cells are responsible for moderating the inflammatory response by
angiogenesis and tissue remodeling
- The M2 cells are
associated with an immune response by secreting the factors IL-10 or TGF-β
angiogenesis and tumor growth by secreting IL-23, fibroblast growth
factors (FGFs), IL-17, vascular endothelial growth factors (VEGFs).
Study on Cell Lines
macrophage cell lines it was found that the albumin in nab-paclitaxel allowed
the drugs to enter the macrophages through macropinocytosis which made this
drug more effective than paclitaxel. Studies conducted on mice with pancreatic cancer
showed that once the
drug nab-paclitaxel entered macrophages, they changed from suppressing tumor
response (M2 cells) into multiplying the immune response against cancer cells
postdoctoral fellow in Bar-Sagi's lab, Dr. Jane Cullis who is the lead author
of the study said that the findings show that the treatment target macrophages
by associating albumin with immune activating agents. This could give rise to
drugs that alter the structure of albumin, making it last
longer in macrophages. Alternatively, drug therapy for cancer could involve a
combination of Abraxane with T cell therapy for better results. Such form of
therapy will prove to be effective in treatments against certain tumors that
consist of infiltration of a large amount of macrophages.
infiltrate a large number of cancer cells
different types of cancers and a system that aids in switching the type of
macrophages into a cancer-fighting response could improve treatment of cancer.
- Jane Cullis, Despina Siolas, Antonina Avanzi, Sugata Barui, Anirban Maitra, Dafna Bar-Sagi. Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer. Cancer Immunology Research, 2017; DOI: 10.1158/2326-6066.CIR-16-0125
- Role of Macrophages in Malignancy - (https:www.ncbi.nlm.nih.gov/pmc/articles/PMC3591014/)