- Immunotherapy is
a treatment that uses the body's own cells (immune cells) to fight cancer.
- Using checkpoint
inhibitors like PD-1 for immunotherapy are only effective against a
minority of cancer patients.
- Novel CRISPR-Cas9
screening system developed to identify genes that make cancer cells more
susceptible to checkpoint inhibitors.
Immune checkpoint inhibitors are drugs that are used
in immunotherapy to treat cancer. However, checkpoint inhibitors like PD-1 are
effective only in a minority of cancer patients. Researchers have been trying
to identify if other drugs, when combined with PD-1, are able to destroy cancer
cells in more number of patients. A novel screening system developed by a team
from Dana-Farber/Boston Children's Cancer and Blood Disorders Center using
has paved the way for the discovery of new
drug targets that may aid in cancer immunotherapy.
Cancer Immunotherapy and Checkpoint Inhibitors
is a commonly used treatment
option for cancer. It is also called biotherapy or biological therapy. Here the
patients' own immune system is used to fight the cancer. This is done by either
stimulating the immune cells to work harder or by introducing man-made immune
proteins in the patient.
‘Deletion of Ptpn-2 gene from melanoma cancer cells in mice made them more susceptible to the PD-1 checkpoint inhibitor.’
An individual's immune system is responsible for destroying
all foreign materials or organisms that enter the body. It does so with the
help of cells called immune cells. Immune cells to some extent protect the body
from cancer also. However, this is limited, as the immune cells do not always
recognize the cancer cell as a foreign material. This is because the cancer cells
are not very much different from normal body cells or the immune response is
not strong enough to destroy the cancer cells. Sometimes the cancer cells
themselves apply a "brake" to evade the immune attack.
are drugs that switch off the "brakes", which helps the
immune cells to recognize and attack the cancer. Examples of these include PD-1
However, PD-1 is effective in only a minority of cancer
patients. This study published in Nature
was able to identify targets
that made the cancer cells more susceptible to PD-1 using a novel screening
Novel CRISPR-Cas9 in-vivo Genetic Screening Method
cells were genetically modified to express Cas9 enzyme that
cuts the DNA. 2,368 genes expressed in melanoma cells were tested to identify
if they increase susceptibility of cancer cells to PD-1 or help in evasion.
CRISPR was used to knock out each one of the 2,368 genes. Once the genes were
knocked out, they were put into a mouse to crate a tumor. Each mouse model was
further provided immunotherapy (PD-1 checkpoint inhibitors) to help fight the
cancer cells. If a maximum number of cancer cells were destroyed, it meant that
the gene that was knocked out in that mouse model made the cancer cells more
susceptible to the PD-1 immunotherapy.
Using this screening
method, several previously undiscovered immunotherapy targets were discovered.
Deletion or knocking out of Ptpn-2 gene markedly increased the response of the
tumors to immunotherapy. This in turn means that if a drug is invented to
specifically block or delete the Ptpn-2 gene in cancer cells, then the cancer
cells may easily be destroyed in a majority of patients through immunotherapy.
Senior author Haining said "Deleting Ptpn-2 ramps up
those immune signaling pathways, making tumor cells grow slower and die more
easily under immune attack." Future prospects
vivo genetic screens in tumor models can identify new immunotherapy
be applied to all cancers including renal, colon, lung and other cancers.
of drugs that induce a loss of function in the Ptpn-2 gene.
- Manguso, R. T., Pope, H. W., Zimmer, M. D., Brown, F. D., Yates, K. B., Miller, B. C., Haining, W. N. (2017). In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. doi:10.1038/nature23270