Nature: A genetic map of cancer immune escape.

Over the past decade, different forms of immunotherapy have become truly effective cancer treatments, and cancer immunotherapy, represented by PD-1/PD-L1 inhibitors, has revolutionized the field of cancer.
, however, immunotherapy produces a lasting response in only a limited number of patients, not for all cancer types.
cancer cells develop so-called cancer resistance mutations that lead to a worsening response to treatment, it is important to understand at the molecular level how cancer develops resistance to immunotherapy and makes cancer immunotherapy more widely available.
September 23, 2020, the latest issue of Nature magazine published online a research paper by Jason Moffat of the University of Toronto, Canada, entitled: Functional Genomic Landscape of cancer-intrinsic evasion of killing by T cells. Using CRISPR screening, the
team screened six mouse tumor cells for breast, colorectal, kidney and melanoma and successfully identified 182 "core cancer inherent immune escape genes" that make cancer cells more sensitive or resistant to T-cell attacks.
the study successfully mapped the cancer immune escape gene, paving the way for the development of immunotherapy.
In immunotherapy, CAR-T therapy, which transforms cancer patients' own immune cells (lethal T-cells) to detect and destroy cancer cells, has achieved great success in blood cancers such as leukemia and lymphoma, but for most cancer patients, especially solid tumor patients, CAR-T therapy has not worked well.
is a war between the immune system and cancer cells, which try to find and kill cancer cells, while cancer cells try to escape the immune system's lethal effects.
different mutations in tumor cells in the body and between individuals can lead to tumor heterogeneity, which affects the response to treatment and complicates cancer treatment.
So it doesn't make much sense to find the genes that cause immune escape in a tumor, and what we need to find is a gene that regulates immune escape in a variety of cancers, which is the best treatment target.
team used CRISPR screening techniques to look for genes that regulate immune escape from six genetically diverse tumor models: breast cancer (4T1, EMT6), colorectal cancer (CT26, MC38), kidney cancer (Renca) and melanoma (B16).
team successfully identified 182 "inherent immune escape genes for core cancers" that make cancer cells more sensitive or resistant to T-cell attacks.
team found that these genes that enhance cancer immune escape contain mutation genes that are currently present in all cancer patients who have been confirmed to be ineffective in immunotherapy, further demonstrating the effectiveness of the method.
182 "inherent immune escape genes" for core cancers, many of which have not previously been found to be linked to immune escape.
this means that the map of the cancer's immune escape gene contains a wealth of new biological information.
autophagy is the process by which cells accelerate the recycling of their ingredients to reduce post-stress damage, and autophagy-related genes are key to immune escape, so it seems feasible to target autophagy to increase cancer sensitivity to immunotherapy.
, however, the team went further and found that the removal of certain autophagy genes in pairs can make cells resistant to immune system damage.
means that if a tumor already has a autophagy mutation, combining immunotherapy with a drug that targets another autophagy gene can worsen the patient's disease.
this was never expected before.
More importantly, the study suggests that the multi-effects of autophagy pathogenes can lead to the failure of immunotherapy targeting individual genes, and the genetic background and mutations that already exist largely determine whether the introduction of a second mutation is ineffective, increased resistance, or increased sensitivity to immunotherapy.
Overall, the study identified a core set of conservative genes and pathf paths for cancer immune escape by screening functionally and genetically different tumor cell lines, paving the way for the development of immunotherapy.
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