Nat Commun: French scientists have discovered a new drug-resistant treatment strategy for cancer immunotherapy.

The use of the immune system to fight disease began at least 300 years ago.
, the wife of a British diplomat observed in Istanbul in 1718 that "human pox vaccination" was very popular there.
this means grinding the pox scars of smallpox patients into powder, or getting pus directly from the patient so that they can come into contact with normal people.
people didn't know how the immune system works, but they knew it would cut the fatality rate from up to 30 percent to 1 to 2 percent.
many important scientific breakthroughs, often initially from lucky discoveries.
In the cases of bovine pox vaccine, the reduced activity of pathogens is a good starting point for vaccine development, and the pathogens that Dr. Jenner used to inoculate at that time, its activity has been naturally "reduced", both to bring an immune response without infection, is a very lucky event.
the discovery of PD-1 is another lucky event in the history of human science, PD-1, in the early 1990s.
this accidental discovery has also had a profound impact on future generations.
, however, it was in 1999 that a team of professors decided to knock out the PD-1 gene in mice to explore its function.
interestingly, half of mice lacking PD-1 developed lupus-like symptoms, a serious autoimmune disease.
the researchers concluded that the immune system in the mice was abnormally activated.
, PD-1 plays a role in suppressing the immune system in mice.
, such as Professor Ben-Yu, quickly realized that PD-1 could be a similar "immune brake" or could have a specific effect on tumor immunity.
chinese scientist Professor Tsing Ping's discovery of PD-1's liant PD-L1 (B7-H1) on tumor cells points to a viable path.
2002, Professor Ben yu published a paper clarifying that inhibiting PD-1 path paths in mice can greatly enhance their resistance to tumors.
the growth of melanoma cells was significantly inhibited by PD-L1 antibodies.
in mice lacking PD-1, melanoma cells were completely suppressed.
"These results show that... Inhibiting the combination of PD-1 and PD-L1 has the hope of bringing immunotherapy to specific tumors.
," the researchers wrote in the abstract.
Inevitable events: The development of resistance brought about by PD-1 antibody-specific therapy, from the discovery of PD-1 gene function to today's hot immuno-checkpoint inhibitor therapy, all seem to be water-to-water development.
, however, both clinicians and researchers face a huge challenge: treatment with PD-1 antibody blockers, and there are still patients with tumor recurrence and resistance.
this fact seems extremely depressing, the emergence of immuno-checkpoint inhibitor therapy (ICB) to resist the drug-resistant development brought about by traditional cancer treatments, such as chemotherapy, so who can resist the recurrence of tumors caused by ICB? The answer, perhaps, can be drawn from a French team's research.
selective inhibition of GARP-Tregs produces TGF-beta 1, which resists tumor resistance to PD-1/PD-L1 blockers September 11, 2020, Catholic Church in Leuven, France Professor Sophie Lucas of the University's team published a research paper in the journal Nature Communications entitled Selective Regency of TGF-beta-1 produced by GARP-expressing Tregs overcomes to PD-1/PD-L1 blockade in cancer.
study, the authors found that anti-GARP:TGF-beta-1mAb, in combined with PD-1 blockers, significantly enhanced the effects of tumor T cells and prevented tumor recurrence.
the GARP gene, a molecule found by Professor Lucas on the surface of Treg cells in 2009, has been exploring its function for years.
2018, she discovered that the molecule acted as a messenger for Treg cells, sending signals to prevent immune responses from occurring.
important findings were published in the November 23, 2018 issue of The Science Journal (Science, 2018, doi: 10. 1126/science.aau2909).
the key to developing resistance after treatment with PD-1 blockers is that the immunosuppression of Treg cells is essential for maintaining external immune tolerance, but plays the opposite role in chronic infections and cancers.
targeting Treg cells to treat cancer is a popular but still pending area of cancer immunotherapy.
There have been studies that have shown that Tring cells in mice can be mediated by a variety of mechanisms, but it is not clear whether targeting these mechanisms can increase anti-tumor immunity in cancer patients, while currently available cancer immunotherapy cannot specifically block Treg without harming other lymphocytes in the TEM.
known to produce the immunosuppressive factor TGF-beta 1 in Treg cells that can be specific to mAb.
Treg produces TGF-beta1 in an inactive form, which is non-co-priced with latent-related peptides (LAPs) on the surface of its membrane to form a polymer ring structure.
With the signal stimulation of TCR, only GARP-Treg cells can release TGF-beta 1 from the LAP ring, because GARP can form a desulfur bond with LAP, thereby releasing the bits on TGF-beta1 that bind to the subject.
professor Sophie Lucas believes that the release of TGF-beta 1 from the LAP ring by GARP-Treg cells is a key link in tumor immunotherapy, where tumor cells develop resistance.
anti-GARP: TGF-beta-1mAb, in combined with PD-1 blockers, significantly enhances the effectiveness of tumor T-cells To solve this problem, the team built anti-rat GARP: TGF-beta 1mAb and mouse colon cancer models.
In mouse models, the combined use of RAT GARP:TGF-beta-1mAb with PD-1 blockers significantly prolonged the survival of mice, slowed tumor growth, and even achieved complete tumor relief in some individuals.
researchers inoculated colon cancer cell strains here 46 days after the completely relieved mouse tumor disappeared, but found a recurrence of colon cancer.
Anti-GARP: TGF-beta1 and anti-PD-1 combinations induce mice to produce a memory-based immune response to the same tumor antigen to prevent tumor recurrence, and researchers have found in further experiments that the enhanced effect of this combination therapy is not achieved by increasing CD8-T cells or reducing the number of Trig cells.
the desired therapeutic effect only by amplifying the anti-tumor immune activity of the T cells themselves.
, they also detected the presence of GARP-Treg cells in a variety of human tumors, especially melanoma.
'The combination therapy of anti-GARP:TGF-beta-1 and anti-PD-1 is effective by amplifying the activity of CD8-plus cells and releasing IFN gamma signals,' the authors write at the end of the article.
However, this does not necessarily mean that anti-GARP: TGF-beta-1mAb has no anti-tumor activity as a monotherapy in cancer patients, only that they can overcome the body's primary or obtained resistance to PD-1/PD-L1.
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