The mechanisms of controlling programmed death ligand-1 (PD-L1) at the transcription and protein acetylation levels in promoting breast cancer growth are presented. Overexpressed PD-L1 accelerated breast cancer growth in vitro and in vivo.
[Acta Pharmacologica Sinica]
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By using the Eµ-TCL1 adoptive transfer mouse model of chronic lymphocytic leukemia, scientists observed that ibrutinib effectively controled leukemia development, but also resulted in significantly lower numbers of CD8+ effector T-cells, with lower expression of activation markers, as well as impaired proliferation and effector function.
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Hanna, B. S., Yazdanparast, H., Demerdash, Y., Roessner, P. M., Schulz, R., Lichter, P., Stilgenbauer, S., & Seiffert, M. (2021). Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice. Haematologica, 106(4), 968–977. https://doi.org/10.3324/haematol.2019.238154 Cite
Merck announced that the FDA has issued a Complete Response Letter regarding Merck’s supplemental Biologics License Application seeking approval for KEYTRUDA, the company’s anti-PD-1 therapy, for the treatment of patients with high-risk early-stage triple-negative breast cancer, in combination with chemotherapy as neoadjuvant treatment, then continuing as a single agent as adjuvant treatment after surgery.
[Merck (BusinessWire, Inc.)]
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Hutchison China MediTech Limited has initiated a Phase Ib/II study of surufatinib in combination with BeiGene’s tislelizumab in patients with advanced solid tumors in the US and Europe.
[Hutchison China MediTech Limited]
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Researchers investigated the maturation of the CD8+ T cell compartment in human fetal, infant and adult intestinal tissues. CD8+ T cells exhibiting a memory phenotype were already detected in fetal intestines and increased after birth.
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Schreurs, R. R. C. E., Sagebiel, A. F., Steinert, F. L., Highton, A. J., Klarenbeek, P. L., Drewniak, A., Bakx, R., The, S. M. L., Ribeiro, C. M. S., Perez, D., Reinshagen, K., Geijtenbeek, T. B. H., van Goudoever, J. B., & Bunders, M. J. (2021). Intestinal CD8 + T cell responses are abundantly induced early in human development but show impaired cytotoxic effector capacities. Mucosal Immunology, 1–10. https://doi.org/10.1038/s41385-021-00382-x Cite
CCR8 was expressed by Tregs in both murine and human tumors, and unlike CCR4, a Treg depletion target in the clinic, CCR8 was selectively expressed on suppressive tumor Tregs and minimally expressed on proinflammatory effector T cells
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Campbell, J. R., McDonald, B. R., Mesko, P. B., Siemers, N. O., Singh, P. B., Selby, M., Sproul, T. W., Korman, A. J., Vlach, L. M., Houser, J., Sambanthamoorthy, S., Lu, K., Hatcher, S. V., Lohre, J., Jain, R., & Lan, R. Y. (2021). Fc-optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-20-3585 Cite
Investigators demonstrated that the expression of BCL9 and BCL9L was directly correlated with malignancy in TNBC patient tumors and that BCL9 and BCL9L promoted tumor cell growth, cell migration and metastasis in TNBC models.
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Wang, X., Feng, M., Xiao, T., Guo, B., Liu, D., Liu, C., Pei, J., Liu, Q., Xiao, Y., Rosin-Arbesfeld, R., Shi, Y., Zhou, Y., Yang, M., Feng, Y.-X., Jiang, Y., Shao, Z., Yu, K., & Zhu, D. (2021). BCL9/BCL9L promotes tumorigenicity through immune-dependent and independent mechanisms in triple negative breast cancer. Oncogene, 1–16. https://doi.org/10.1038/s41388-021-01756-y Cite
Scientists demonstrated that enhancer of zeste homolog-2 (EZH2) inhibition in prostate cancer models activated a double-stranded RNA–STING–ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that was dependent on STING activation.
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Morel, K. L., Sheahan, A. V., Burkhart, D. L., Baca, S. C., Boufaied, N., Liu, Y., Qiu, X., Cañadas, I., Roehle, K., Heckler, M., Calagua, C., Ye, H., Pantelidou, C., Galbo, P., Panja, S., Mitrofanova, A., Wilkinson, S., Whitlock, N. C., Trostel, S. Y., … Ellis, L. (2021). EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nature Cancer, 1–13. https://doi.org/10.1038/s43018-021-00185-w Cite
Scientists demonstrated that although inhibition of xCT either by pharmacological inhibitor, approved by FDA for inflammatory diseases, or genetic knockdown induced ROS-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and, reduced the efficacy of anti-PD-1/anti-PD-L1 therapy in melanoma.
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Liu, N., Zhang, J., Yin, M., Liu, H., Zhang, X., Li, J., Yan, B., Guo, Y., Zhou, J., Tao, J., Hu, S., Chen, X., & Peng, C. (2021). Inhibition of xCT Suppresses the Efficacy of Anti-PD-1/-L1 Melanoma Treatment through Exosomal PD-L1 Induced Macrophage M2 Polarization. Molecular Therapy, 0(0). https://doi.org/10.1016/j.ymthe.2021.03.013 Cite
The authors describe the immunosuppressive molecular characteristics of recurrent glioblastoma; clinical trials exploring anti-PD-1/PD-L1 therapy, tumor-specific peptide vaccination, and CAR-T cell therapy; candidate combination strategies; and issues related to strengthening T cell function.
[Cell Death & Disease]
Flow cytometry analyses revealed a higher EOMES expression in CD8+ T cells of chronic lymphocytic leukemia (CLL) patients compared to healthy individuals, and an accumulation of PD-1+ EOMES+ CD8+ T cells in lymph nodes rather than blood or bone marrow in CLL.
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Llaó-Cid, L., Roessner, P. M., Chapaprieta, V., Öztürk, S., Roider, T., Bordas, M., Izcue, A., Colomer, D., Dietrich, S., Stilgenbauer, S., Hanna, B., Martín-Subero, J. I., & Seiffert, M. (2021). EOMES is essential for antitumor activity of CD8 + T cells in chronic lymphocytic leukemia. Leukemia, 1–11. https://doi.org/10.1038/s41375-021-01198-1 Cite