Cell: to reveal the mechanism of bone metastasis of prostate cancer through TGF - β resistance immunotherapy

November 20, 2019 / Biovalley BIOON / - -- in a new study, researchers from MD Anderson Cancer Center at the University of Texas reported that prostate cancer spreading to bone can cause bone tissue damage, thus hindering the development of T cells, which will undermine the effectiveness of immune checkpoint inhibitors, after all, T cells are crucial to the success of treatment This finding reveals why immunotherapy is largely unsuccessful in the treatment of prostate cancer with bone metastases, and suggests that combination therapy may reverse this resistance Relevant research results were published in the cell Journal on November 14, 2019, and the title of the paper is "differences in tumor microenvironment differentiated T helper lineage polarization and response to immune checkpoint therapy" The corresponding author is Dr padmanee Sharma, Professor of reproductive urology oncology and professor of immunology, MD Anderson Cancer Center, University of Texas Picture from cell, 2019, DOI: 10.1016/j.cell.2019.10.029 Their findings also highlight the need to look at metastatic cancer in a different light "We tend to think of stage 4 diseases as unified, but not all of them," Sharma said We need to think more about the immune microenvironment of different sites of metastasis in order to take into account the different immune responses in these microenvironments when we develop treatments " The study points to the combination of anti TGF - β and anti-CTLA-4 Sharma and his team found that bone destruction caused by tumor resulted in the production of transforming growth factor - β (TGF - β), a protein that can cause helper T cells (Th cells) to polarize into Th17 CD4 cells, rather than Th1 CD4 effector cells required to trigger anti-tumor immune response Anti TGF - β therapy combined with CTLA-4 checkpoint inhibitor can inhibit the growth of bone metastases in mice model "We are working to develop clinical trials of anti-CTLA-4 and anti TGF - β in the treatment of metastatic prostate cancer," Sharma said Most men with prostate cancer develop into metastatic castration resistance disease, which is almost fatal About 70% - 80% of men with stage 4 prostate cancer have bone metastasis Although recent studies by Sharma and his colleagues have shown that the combination of anti-CTLA-4 and anti-PD-1 immunocheckpoint inhibitors (ipilimumab, ipilimumab, nevumab) can help some male patients with stage 4 prostate cancer, it has basically failed in preventing bone metastasis To understand this, the Sharma team first looked at the bone marrow of patients before and after treatment to get clues about treatment resistance They further studied the observations in a mouse model of metastatic prostate cancer and tested the combination therapy When the deficiency of Th1 CD4 T cells works, the blocking of immune checkpoint will lead to the proliferation of Th1 CD4 effector cells, which in turn leads to the activation of killer CD8 T cells and the production of long-term memory cells Sharma's team found a large number of Th1 effector cells in the soft tissues of patients treated with iprimma, but these most important cells are basically absent in the bone, on the contrary, they found a large number of Th17 cells there "It's important that there are no Th1 cells in the bone," Sharma said Cytokines polarize helper T cells into different types, and they produce a large number of Th17 cells in bone microenvironment The function of Th17 cells is not clear Sharma's team built two models of metastatic disease in mice - one for bone metastasis and the other for primary prostate cancer or soft tissue metastasis As in human patients, the combination of iprimma and nafumab can reduce tumor size and prolong the survival of mice with soft tissue metastasis, but has little effect on the survival of primary prostate and bone metastasis mice The tumor infiltrating CD4 and CD8 T cells in soft tissue and bone proliferated, but failed to inhibit the growth of bone metastasis These T cells were analyzed by mass spectrometry and flow cytometry There are only Th17 and Treg cells in the CD4 T cells of bone metastasis, but there are no Th1 cells in bone metastasis Treg cells inhibit the immune response In the subcutaneous model, Th1 effector cells were detected before treatment, then increased significantly after treatment, while Th17 cells and Treg cells decreased The lack of TGF - β to protect Th1 cells in bone marrow suggests that the cytokine profiles in bone microenvironment are different Sharma's team analyzed the levels of 13 cytokines in the tumor bearing and tumor free femurs of mice They found that a significant increase in TGF - β inhibited Th1 cell lineage and promoted Th17 and Treg cell production Th17 cells also need the presence of IL-6, which is expected to be high in bone marrow Bone metastasis triggers abnormal bone remodeling, and bone components are known as the main reservoir of TGF - β Sharma's team speculated that bone matrix remodeling resulted in higher TGF - β levels in prostate bone metastases Their experiments confirm that tumor activated osteoclasts release excessive TGF - β while eroding the bone surface To test this conjecture in humans, they compared bone marrow TGF - β levels in healthy donors and prostate cancer patients with or without bone metastasis There was no difference in the level of TGF - β between the healthy controls and the patients without bone metastasis, while the level of TGF - β in the bone of the patients with bone metastasis was abnormally high Blocking TGF - β can restore Th1 cells and enhance the combination of immunotherapy with ipprimma and nevumab, but adding anti TGF - β to this combination therapy can prevent tumor growth The combination therapy of anti TGF - β and iprimma also inhibited the growth of bone metastasis In the bone microenvironment, this combination also increased the frequency of Th1 cells and decreased Treg cells (BIOON Com) reference: 1.shipping Jian et al Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy Cell, 2019, doi:10.1016/j.cell.2019.10.029 2.Prostate cancer bone metastases thwart immunotherapy by producing TGF-beta https://medicalxpress.com/news/2019-11-prostate-cancer-bone-metastases-thwart.html