PROTECTION OF T-LYMPHOCYTES VIA PD-1 RECEPTOR: NEW MOLECULAR MECHANISM OF CANCER IMMUNOTHERAPY
After briefl y reviewing major forms of cell death and discovery of programmed (cell) death 1 (PD-1) protein and its ligands (PD-L1 and PD-L2), this overview is focused on how PD-1 and PD-1 ligands are involved in a new form of in immunosuppression that represents a new approach to cancer therapy. Namely, tumor cells often kill cytotoxic T lymphocytes through PD-1 mechanisms – hence, PD-L1 inhibitors represent a new molecular mechanism of cancer immunotherapy. Recent translational clinical research also revealed a substantial infl uence of gut microbiome on response to PD-1-based cancer immunotherapy. The initial discovery was that cancer patients treated with antibiotics for various infections have diminished response to anti-PD-1 therapy. Comparing the fecal microbiota of responders to non-responders revealed increased abundance of Akkermansia muciniphila, Faecalibacteria and Bifi dobacteria in patients showing favorable outcomes to anti–PD-1 treatment.
Conclusions: 1. Recent studies revealed how inhibition of certain cell death (e.g., cytotoxic T cells) via PD-1 leads to increased death of tumor cells. 2. The eff ectiveness of PD-1-based cancer immunotherapy is greatly infl uenced by gut microbiome (e.g., fi rmicutes and clostridia have positive, while bacteroidia exert negative eff ects). 3. Nevertheless, checkpoint inhibitors (via PD-1, PD-L1) represent a new and eff ective cancer immunotherapy, even in metastatic melanoma. 4. Thus, the discoverers of PD-1 and PD-L1 rightly shared the 2018 Nobel Prize in Physiology or Medicine.
Ishida Y, Agata Y, Shibahara K, Honjo T (November 1992). "Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death". The EMBO Journal. 11 (11): 3887-95.
Bardhan K, Anagnostou T, Boussiotis VA (2016). "The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation". Frontiers in Immunology. 7: 550. doi:10.3389/fimmu.2016.00550. PMC 5149523. PMID 28018338
Leach, D. R., Krummel, M. F., & Allison, J. P. (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271, 1734-1736.
Okazaki T, Honjo T. PD-1 and PD-1 ligands - from discovery to clinical application. Int Immunol, 2007,19, 813-24.
Salmaninejad A et al. PD-1 - PD-L1 pathway - Basic biology and role in cancer immunotherapy. J. Cell Physiol. 2019, 234(10),16824-16837.
Sharpe AH, Pauken KE. The diverse function of the PD-1 inhibitory pathway. Nature Rev. Immunol., 2018, 18, 153-167.
Szabo S, Deng X, Khomenko T, Chen L, Tolstanova G, Osapay K, Sandor Z, Xiong X. New molecular mechanisms of duodenal ulceration. Ann N Y Acad Sci., 2007; 1113:238-55.
Szabo S, Yoshida M, Filakovszky J, Juhasz Gy. "Stress" is 80 years old: From Hans Selye original paper in 1936 to recent advances in GI ulceration. Curr. Pharm. Des. 2017; 23:4029-4041.
Jadus MR, Natividad J, Mai A, Ouyang Y, Lambecht N, Szabo S, Ge L, Hoa N, DaCosta-Iyer MG. Lung cancer: A classic example of tumor escape and progression while providing opportunities for immunological intervention. Clin. Developm. Immunol. 2012, Article ID 160724, 21 pages, Epub 2012 Jul 29.
T-lymphocyte & cancer interaction: https://www.immunooncologyhcp.bmsinformation.com/antitumor-immunity/pathways/PD1-pathway?cid=sem_192657&ovl=blank
Krummel M. Nobel notes value of basic research for new drugs. Nature, 2018, 563, 184.
Grady D.: Harnessing the immune system to fight cancer. New York Times, July 30, 2016: https://www.nytimes.com/2016/07/31/health/harnessing-the-immune-system-to-fight-cancer.html?_r=0
Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways. Am. J. Clin Oncol. 2016,39,98-106.
Gopalakrishnan V et al. Gut microbiome modulates response to anti-PD-1 immunotherapy melanoma patients. Science, 2018, 359, 97-103.
Matson V et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science, 2018, 359, 104-108.
Routy B et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2018, 359, 91-97.
Jobin C. Precision medicine using microbiota. Intestinal microbiota influence cancer patient responses to immunotherapy. Science,2018,359,32-34.
Dolan DE, Gupta S. PD-1 Pathway Inhibitors: Changing the landscape of cancer immunotherapy. Cancer Control, 2014, 21, 231-237.
Ledford H. Many cancer drugs aim at the wrong molecular targets. Nature, 2019, 573, 151-153.
Szabo S, Szabo K. Zayachkivska O. Stress: From HS to today… Ukr. Edition 2019
Abstract views: 168 PDF Downloads: 73