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In 2018, the Nobel Prize in Physiology or Medicine was awarded to James Ellison (James Allison) Professor and Prof. Benjamin In recognition of their outstanding contributions in the field of cancer immunotherapy. Few people know that Professor Ellison’s wife, Padmanly Sharma, is a study of cancer immunotherapy. Excellent scientists, the two are lifelong partners.

Image Source: Shama Professor Personal Lab Homepage Screenshot

Today, Professor Shama’s team published an important study in the top academic journal Cell, revealing how the tumor microenvironment can interfere with the effectiveness of cancer immunotherapy. In addition, they have found potential solutions to this problem. “Cell” magazine has specially compiled a special article for this paper, the importance of which can be seen.

The cause of this study comes from an interesting clinical observation. Scientists have discovered that the condition has changedShifting castration-resistant prostate cancer (a very deadly prostate cancer) in patients, if cancer has metastasized to the bone, classic immunotherapy The effect is extremely limited. Interestingly, if only transferred to soft tissue, the patient’s treatment is much better. Why is this?

From the bone marrow of these patients, the researchers extracted samples for the study. In theory, under the influence of immunotherapy, the number of Th1 helper cells should increase sharply, promoting the activation of CD8-positive immune T cells, thereby attacking the tumor. This phenomenon was reconfirmed in patients who only stayed in soft tissue. However, in patients who have metastasized to bones, the number of other helper cells, Th17, has increased significantly. Instead, the researchers barely saw the shadow of Th1 helper cells.

“Cell” magazine commented on this article (Source: Reference [2])

“The key here is the lack of Th1 helper cells,” Dr. Shama said. She pointed out that different cytokines determine which different types of helper cells will differentiate. There are so many Th17 helper cells, indicating that there must be many cytokines that promote the differentiation of such cells in the patient’s bones.

So, what is this mysterious cytokine? In the mouse model, the researchers analyzed the levels of 13 different cytokines. Among them, a cytokine called TGF-β has a marked rise. Interestingly, it has previously been known that it can limit the differentiation of Th1 helper cells and promote the production of Th17 helper cells and regulatory T cells, a class of cells that suppress the immune system.

Next, the researchers clarified the mechanism behind it – a cell called “osteoclasts” was activated under the influence of tumors. As the name implies, it “destroys” bone tissue. As the saying goes, it doesn’t break, in the usual situationThese cells play an important role in the repair and stabilization of bone tissue. But in the presence of tumors, it has become an accomplice to cancer cells.

Illustration of this study (Source: Reference [1])

There is a large amount of TGF-β in the bone tissue, and the activated osteoclasts release them, promoting the production of Th17 helper cells and regulatory T cells, and inhibiting the differentiation of Th1 helper cells. Consistent with this hypothesis, healthy people and patients with tumors that have not yet metastasized to bones have similar levels of TGF-β in the body. Once the tumor has metastasized to the bone, the level of TGF-β will soar.

What’s even more gratifying is that although the classic immunotherapy combination does not inhibit tumor growth in bone metastases, we can magically stop the tumor from growing in mice as long as additional TGF-β-targeting drugs are added.

Adding drugs against TGF-β in specific situations can make immunotherapy more effective (Source: Reference [2])

“We thought that the cancers that entered Stage IV were the same, but they were not the same,” Professor Shama said. “We need to think about the immune microenvironment of different metastatic sites, and when developing therapies. Take into account the different immune responses of these microenvironments.”If we can treat the environment against different tumor microenvironments, we may be able to further improve the effectiveness of immunotherapy in cancer patients. After all, only about 20% of patients can benefit from this Nobel Prize breakthrough, and there is still a long way to go.

References:

[1] Shiping Jiao et al, (2019), Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy, Cell, DOI:. Https: // Doi.org/10.1016/j.cell.2019.10.029

[2] Vincenzo Bronte, (2109), Close to the Bone: Tissue-Specific Checkpoint Immunotherapy Evasion, Cell, DOI: https: //doi.org/10.1016/j .cell.2019.10.022

[3] Prostate cancer bone metastases thwart immunotherapy by producing TGF-β, Retrieved November 14, 2019, from https://www.eurekalert.org/pub_releases/2019-11 /uotm-pcb111219.php

Article from WeChat public account:Academic latitude (ID: Global_Academia)