Cancer immunology drugs, which harness the body's immune system to better attack cancer cells, have significantly changed the face of cancer treatment. People with aggressive cancers are now living longer, healthier lives. Unfortunately, cancer immunology therapy only works in a subset of patients.
Now, a new study from scientists helps explain why some people with advanced cancer may not respond to one of the leading immunotherapies, PD-1 blockade, and how a new combination approach may help overcome resistance to the immunotherapy drug.
The study published in the inaugural issue of the new scientific journal Nature Cancer, showed that genetic and pharmacological inhibition of the oncogene PAK4 overcomes resistance to anti-PD-1 therapy in preclinical models.
"One of the main reasons patients do not respond to PD-1 blockade is because the T cells never make it into the tumor to attack the cancer cells," said lead author. "We found that biopsies of patients who did not respond to PD-1 blockade showed an overexpression of PAK4, so that led us to believe it played a role in suppressing the immunotherapy treatment."
PAK4 has been known previously to be involved in cell migration and proliferation. The new research demonstrates that high expression of this oncogene also correlates with a lack of immune cells migrating into the tumors to destroy the cancer cells.
Using biopsies from people with advanced melanoma who received the immune checkpoint blocking antibody pembrolizumab, researchers performed RNA sequencing to characterize the phenotype of the tumors. They saw that the tumors that did not respond to PD-1 blockade had a high expression of PAK4 and were not infiltrated by immune cells, meaning that the immune cells had not found their way to the tumor to attack the cancer cells.
The team then inhibited PAK4 in cell lines by either using a drug inhibitor or a gene editing technique called CRISPR-Cas9. The scientists found that deleting PAK4 increased the migration of tumor-specific immune cells and sensitized tumors to PD-1 blockade immunotherapy, reversing the resistance.
"Developing new and improved combination treatments like this one for people who do not initially respond to anti-PD-1 treatment is the next step forward in our efforts to make immunotherapy work better for more people," said the study’s senior author. "The results from this study could also be expanded to other tumor types that are notoriously resistant to PD-1 blockade, such as pancreatic cancer."
The PAK4 inhibitor used in the study is already being tested in a phase one trial. The combination treatment with anti-PD-1 will be tested in a clinical trial setting in the near future.
https://www.uclahealth.org/ucla-study-shows-inhibition-of-gene-helps-overcome-resistance-to-immunotherapy
https://www.nature.com/articles/s43018-019-0003-0
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fpak4-inhibition&filter=22
Inhibiting a gene to overcome resistance to immunotherapy
- 3,312 views
- Added
Edited
Latest News
More influence of environme…
By newseditor
Posted 24 Apr
The assembly of the human c…
By newseditor
Posted 24 Apr
Wiring of the human neocortex
By newseditor
Posted 24 Apr
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Other Top Stories
Selective inhibition of peanut-specific antibodies
Read more
A gene implicated in protection against neuroinflammation
Read more
Immune alterations associated with progression of lung cancer
Read more
Structure and degradation of circular RNAs regulate PKR activation…
Read more
How scratching may prime children with eczema for food allergy and…
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Massively parallel screen u…
By newseditor
Posted 24 Apr
Distinct genetic and enviro…
By newseditor
Posted 24 Apr
Hippocampus-to-amygdala pat…
By newseditor
Posted 24 Apr
Integrative spatial analysi…
By newseditor
Posted 24 Apr
Time-series reconstruction…
By newseditor
Posted 24 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar