- Scientists identify a molecular switch in an
immune response against cancer that promotes their growth and
- PI-3 kinase gamma suppression found to limit
- The new discovery could improve cancer
immunotherapy, and treatment of Crohn's disease and Alzheimer's.
Scientists have found a way to boost
anti-cancer therapy by identifying a molecular switch which controls immune
suppression in diseases like cancer
, Crohn's disease
. These researchers from The
University of California San Diego hope that this discovery would improve
immunotherapy treatment strategies.
Dr. Judith A. Varner from The University of
California San Diego's Department of Pathology and Medicine said "Immunotherapies,
such as T cell checkpoint inhibitors, are showing great promise in early
treatments and trials, but they are not universally effective.We have
identified a new method to boost the effectiveness of current immune therapy.
Our findings also improve our understanding of key mechanisms that control
cancer immune suppression and could lead to the development of more effective
‘Switching on immune mechanism in cancer will improve response to anti-cancer drugs.’
Immune Suppression in Cancer
In normal human response to injury
at a particular site in the body, macrophages are released, which in turn aid
in the release of certain cytokines. These cytokines activate T- cells that
the invading cells.
In the event of tumor, the
- Tumor lesions or pre-malignant lesions are found to be
infiltered with T-cells and other cells from an immune response.
tumor infiltering cells are part of the body's defence mechanism against the
- These tumor infiltering immune cells are suppressed
by the tumor
- Cytokines and growth factors that are secreted
by these tumor infiltering cells aid in the growth of these tumor cells when
their tumor disrupting activity is weak or absent.
- Further, cytokines that stop the healing process are also
In diseases like Alzheimer's and
Crohn's disease which lead to chronic inflammation, the cytokines and other
cells mediated by an immune response affect normal cells.
PI-3 kinase Gamma (PI3Ky)
Dr. Varner and colleagues have
found that an enzyme from macrophages PI-3 kinase gamma (PI3Ky) is found to
suppress the immune response by blocking the activation of T cells that have
Blocking PI-3 kinase gamma (PI3Ky)
in mice was found to
- Improved immune response to
- Suppressed the growth of tumors that were implanted
- Increased sensitivity of the tumors to anti-tumor
The cancer promoting activity of PI-3
kinase gamma (PI3Ky) validates previous studies that have shown that their
intercellular disruption promotes the growth of cancer by a study conducted by
Attoub S and colleagues and published in The Annals of The New York Academy
. According to this study titled "The transforming functions of
PI3-kinase-gamma are linked to disruption of intercellular adhesion and
promotion of cancer cell invasion", in human colon epithelial cancer cells, the
PI-3 kinase gamma (PI3Ky) lead to alterations in the homotypic cell-cell
adhesion with the invasion of Type I collagen.
The current study by Dr. Varner
and colleagues is aimed at the immune suppression ability of the PI-3 kinase
gamma (PI3Ky) with the identification of a molecular mechanism that is involved
in immune suppression which can be used to modulate immunotherapy.
Moores Cancer Center's Head of
Cancer immunotherapy program, Dr. Ezra Cohen who is also the co-author of the
study said "Recently developed cancer immunotherapeutics, including T cell
checkpoint inhibitors and vaccines, have shown encouraging results in
stimulating the body's own adaptive immune response. But they are effective
only on a subset of patients, probably because they do not alter the profoundly
immunosuppressive microenvironment created by tumor-associated macrophages. Our
work offers a strategy to maximize patient responses to immune therapy and to
eradicate tumors. "
In animal models of pancreatic ductal adenocarcinoma
suppression of PI-3 kinase gamma (PI3Ky) in macrophages associated with tumor
- Tumor cell invasion
When asked about the significance
of identifying newer methods of treatment for cancers, especially pancreatic
ductal carcinoma, assistant project scientist at Dr. Varner's lab, Dr. Megan M.
Kaneda said "PDAC has one of the worst 5-year survival rates of all solid
tumors, so new treatment strategies are urgently needed."
Previous studies by these scientists
on pancreatic ductal carcinoma involved the disruption of signals between B
cells and macrophages that were tumor associated, this leads to
- Disruption in the tumor
- Improved effectiveness of anti-cancer drugs.
This was carried out by the
activation of Bruton tyrosine kinase which resulted in a natural immune
response against tumor cells without any signs of suppression.
The growth and
development of cancers
always been dependent on the body's immune response,which has failed to control
their multiplication. However, such studies throw light on molecular switches
which may be activated to promote tumor growth. A reversal of this switch
should, in theory, be able to restore normal function of the immune response
which would aid in better control over tumor growth.
- Documentaion of Immune Suppression in Cancer Patients
- Immune Suppression in Cancer - (http://www.aimath.org/WWN/tumorimmune/WhitesideImmuneSuppression.pdf)
- Transforming Functions of PI3 Kinase-Gamma Linked
to Disruption of Intercellular Adhesion and Promotion of Cancer Cell
Invasion - (http://www.ncbi.nlm.nih.gov/pubmed/18837901)