Beyond Conventional Immune-Checkpoint Inhibition — Novel Immunotherapies for Renal Cell Carcinoma

Using the structure provided by the well-described cancer–immunity cycle, scientists outline the key steps required for a successful antitumour immune response in the context of renal cell carcinoma, and describe the development of promising new immunotherapies within the context of this framework.
[Nature Reviews Clinical Oncology]
Braun, D. A., Bakouny, Z., Hirsch, L., Flippot, R., Van Allen, E. M., Wu, C. J., & Choueiri, T. K. (2021). Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma. Nature Reviews Clinical Oncology, 1–16. https://doi.org/10.1038/s41571-020-00455-z Cite
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Tumor-Infiltrating Mast Cells Are Associated With Resistance to Anti-PD-1 Therapy

Researchers generated a humanized-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull mice.
[Nature Communications]
Somasundaram, R., Connelly, T., Choi, R., Choi, H., Samarkina, A., Li, L., Gregorio, E., Chen, Y., Thakur, R., Abdel-Mohsen, M., Beqiri, M., Kiernan, M., Perego, M., Wang, F., Xiao, M., Brafford, P., Yang, X., Xu, X., Secreto, A., … Herlyn, M. (2021). Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. Nature Communications, 12(1), 346. https://doi.org/10.1038/s41467-020-20600-7 Cite
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Reprogramming Immunosuppressive Myeloid Cells by Activated T Cells Promotes the Response to Anti-PD-1 Therapy in Colorectal Cancer

The levels of infiltrating myeloid-derived suppressor cells (MDSCs) were significantly higher in the non-responding organoids and were selectively reduced in the responding group, with MDSCs showing increased apoptosis and attenuated functional activity after anti-PD-1 treatment.
[Signal Transduction and Targeted Therapy]
Chen, J., Sun, H.-W., Yang, Y.-Y., Chen, H.-T., Yu, X.-J., Wu, W.-C., Xu, Y.-T., Jin, L.-L., Wu, X.-J., Xu, J., & Zheng, L. (2021). Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer. Signal Transduction and Targeted Therapy, 6(1), 1–14. https://doi.org/10.1038/s41392-020-00377-3 Cite
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Identification of a Subset of Immunosuppressive P2RX1-Negative Neutrophils in Pancreatic Cancer Liver Metastasis

RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism.
[Nature Communications]
Wang, X., Hu, L.-P., Qin, W.-T., Yang, Q., Chen, D.-Y., Li, Q., Zhou, K.-X., Huang, P.-Q., Xu, C.-J., Li, J., Yao, L.-L., Wang, Y.-H., Tian, G.-A., Yang, J.-Y., Yang, M.-W., Liu, D.-J., Sun, Y.-W., Jiang, S.-H., Zhang, X.-L., & Zhang, Z.-G. (2021). Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis. Nature Communications, 12(1), 174. https://doi.org/10.1038/s41467-020-20447-y Cite
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E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling

E7386 demonstrated clear antitumor activity via modulation of the Wnt/β-catenin signal pathway and alteration of the tumor and immune microenvironments, and its antitumor activity could be enhanced in combination with anti-PD-1 antibody.
[Cancer Research]
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Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases

Scientists investigated the impact of chemotherapy on the tumor immune microenvironment. They treated human liver metastases slices with 5-fluorouracil plus either irinotecan or oxaliplatin, then performed single-cell transcriptome analyses.
[Cell Reports Medicine]
Jabbari, N., Kenerson, H. L., Lausted, C., Yan, X., Meng, C., Sullivan, K. M., Baloni, P., Bergey, D., Pillarisetty, V. G., Hood, L. E., Yeung, R. S., & Tian, Q. (2020). Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases. Cell Reports Medicine, 1(9). https://doi.org/10.1016/j.xcrm.2020.100160 Cite
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Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy

Scientists reveal the development of a highly promising therapeutic approach for cancer immunotherapy by targeting PD-1/PD-L1 ubiquitination.
[Molecular Therapy]
Hu, X., Wang, J., Chu, M., Liu, Y., Wang, Z., & Zhu, X. (2020). Emerging role of ubiquitination in the regulation of PD-1/PD-L1 in cancer immunotherapy. Molecular Therapy, 0(0). https://doi.org/10.1016/j.ymthe.2020.12.032 Cite
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Combination of Anti-PD-1 Antibody with P-GEMOX as a Potentially Effective Immunochemotherapy for Advanced Natural Killer/T Cell Lymphoma

Scientists report the efficacy of anti-programmed death 1 antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced natural killer/T cell lymphoma.
[Signal Transduction and Targeted Therapy]
Cai, J., Liu, P., Huang, H., Li, Y., Ma, S., Zhou, H., Tian, X., Zhang, Y., Gao, Y., Xia, Y., Zhang, X., Yang, H., Li, L., & Cai, Q. (2020). Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma. Signal Transduction and Targeted Therapy, 5(1), 1–9. https://doi.org/10.1038/s41392-020-00331-3 Cite
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The Mutational Load and a T-Cell Inflamed Tumor Phenotype Identify Ovarian Cancer Patients Rendering Tumor-Reactive T Cells from PD-1+ Tumor-Infiltrating Lymphocytes

Tumor-reactive tumor-infiltrating lymphocytes were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction.
[British Journal of Cancer]
Salas-Benito, D., Conde, E., Tamayo-Uria, I., Mancheño, U., Elizalde, E., Garcia-Ros, D., Aramendia, J. M., Muruzabal, J. C., Alcaide, J., Guillen-Grima, F., Minguez, J. A., Amores-Tirado, J., Gonzalez-Martin, A., Sarobe, P., Lasarte, J. J., Ponz-Sarvise, M., De Andrea, C. E., & Hervas-Stubbs, S. (2021). The mutational load and a T-cell inflamed tumour phenotype identify ovarian cancer patients rendering tumour-reactive T cells from PD-1 + tumour-infiltrating lymphocytes. British Journal of Cancer, 1–12. https://doi.org/10.1038/s41416-020-01218-4 Cite
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Integrin αvβ6–TGFβ–SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer

The authors identified the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells
[Cancer Cell]
Bagati, A., Kumar, S., Jiang, P., Pyrdol, J., Zou, A. E., Godicelj, A., Mathewson, N. D., Cartwright, A. N. R., Cejas, P., Brown, M., Giobbie-Hurder, A., Dillon, D., Agudo, J., Mittendorf, E. A., Liu, X. S., & Wucherpfennig, K. W. (2020). Integrin αvβ6–TGFβ–SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer. Cancer Cell, 0(0). https://doi.org/10.1016/j.ccell.2020.12.001 Cite
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PD-1 Blockade Improves Kupffer Cell Bacterial Clearance in Acute Liver Injury

The authors found impaired Kupffer cell bacterial clearance and systemic bacterial dissemination in mice with liver injury. Increased PD-1 and PD-L1 expression was detected in Kupffer cells and lymphocyte subsets, respectively, during resolution of injury.
[European Journal of Clinical Investigation]
Triantafyllou, E., Gudd, C. L. C., Mawhin, M.-A., Husbyn, H. C., Trovato, F. M., Siggins, M. K., O’Connor, T., Kudo, H., Mukherjee, S. K., Wendon, J. A., Bernsmeier, C., Goldin, R. D., Botto, M., Khamri, W., McPhail, M. J. W., Possamai, L. A., Woollard, K. J., Antoniades, C. G., & Thursz, M. R. (2020). PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury. The Journal of Clinical Investigation. https://doi.org/10.1172/JCI140196 Cite
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