PD1

Official Full Name

programmed cell death 1

Organism

Homo sapiens

GeneID

5133

Background

Programmed cell death protein 1 (PDCD1) is an immune-inhibitory receptor expressed in activated T cells; it is involved in the regulation of T-cell functions, including those of effector CD8+ T cells. In addition, this protein can also promote the differentiation of CD4+ T cells into T regulatory cells. PDCD1 is expressed in many types of tumors including melanomas, and has demonstrated to play a role in anti-tumor immunity. Moreover, this protein has been shown to be involved in safeguarding against autoimmunity, however, it can also contribute to the inhibition of effective anti-tumor and anti-microbial immunity. [provided by RefSeq, Aug 2020]

Synonyms

PD1; PD-1; CD279; SLEB2; hPD-1; hPD-l; hSLE1; AIMTBS;

Bio Chemical Class

Immunoglobulin

Protein Sequence

MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL

Open

Disease

Bladder cancer, Brain cancer, Breast cancer, Cervical cancer, Colorectal cancer, Diffuse large B-cell lymphoma, Endometrial cancer, Epidermal dysplasias, Esophageal cancer, Follicular lymphoma, Hodgkin lymphoma, Human immunodeficiency virus disease, Inflammatory liver disease, Liver cancer, Lung cancer, Lymphoma, Malignant haematopoietic neoplasm, Melanoma, Metastatic tumour, Multiple myeloma, Myeloproliferative neoplasm, Nasopharyngeal cancer, Neuroendocrine carcinoma, Non-small-cell lung cancer, Oral cavity/oesophagus/stomach in situ carcinoma, Ovarian cancer, Pancreatic cancer, Penile cancer, Pleural mesothelioma, Postoperative inflammation, Prostate cancer, Psoriasis, Renal cell carcinoma, Rheumatoid arthritis, Solid tumour/cancer, Squamous cell carcinoma, Stomach cancer, Ulcerative colitis, Ureteral cancer, Uterine ligament/parametrium/uterine adnexa neoplasm

Approved Drug

9 +

Clinical Trial Drug

50 +

Discontinued Drug

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Detailed Information

PD1 is a type I transmembrane glycoprotein with a molecular weight of 50-55 kD. It belongs to the immunoglobulin superfamily B7-CD28 and is an important immunosuppressive receptor. It is mainly expressed in activated T cells, B cells,and natural killing cells, monocytes, and mesenchymal stem cells. PD1 is an important factor in maintaining self-tolerance. Under physiological conditions, PD1 recognizes antigen through T cell receptor TCR (T cell receptor), regulates the function of T cells in peripheral tissues, and regulates the immune response of the body to foreign or autoantigens, preventing the occurrence of immune-related diseases.

PD-L1 and PD-L2 are ligands for PD1 and are important negative regulators in the immune response. The two functions are similar. The main function is to inhibit cell cycle arrest by inhibiting T cell receptor-mediated B cell proliferation and interleukin 2, 10, interferon gamma and other cytokines by binding to PD1, thereby inhibiting T cell activation.

Figure 1. Effect of PD-1 on major signaling pathways and subsequent metabolic reprograming in T cells. (Kankana, B., et al. 2016)

PD1/PD-L1 and Tumor Immunity

Under normal circumstances, the body's complete immune mechanism can effectively monitor and eliminate cancer cells. Therefore, most individuals do not have tumor growth, and patients with tumors are not prone to distant metastasis. Under physiological conditions, PD-L1 on the surface of normal tissue cells can bind to PD1 on the surface of lymphocytes, inhibit the function of lymphocytes, and induce the apoptosis of activated lymphocytes, thereby preventing autoimmune damage and protecting normal tissues and organs.

Under pathological conditions, the tumor microenvironment induces infiltration of T cells to express PD-1 molecules, and tumor cells highly express PD1 ligands PD-L1 and PD-L2, resulting in continuous activation of PD1 pathway in tumor microenvironment. When PD-L1 linked to PD1, T cell function is inhibited, weakening or blocking its ability to send signals to the immune system that attack the tumor. The PD1/PD-L1 inhibitor can block the binding of PD1 to PD-L1, block the negative regulatory signal, and restore the T cell to activate the immune response. It is shown that blocking PD1 binding to ligands can strengthen and maintain endogenous anti-tumor effects, allowing tumors to be more permanently controlled. Clinical studies have also found that inhibitors of PD1 and PD-L1 have been shown to be effective and well-preserved in a variety of tumors, particularly advanced melanoma and non-small cell lung cancer.

Expression of PD1 in Tumors

PD-L1 is significantly elevated in tumor tissues compared with normal tissues and is expressed on the surface of most tumor cells, including non-small cell lung cancer, melanoma, gastric cancer, colon cancer, breast cancer, pancreatic cancer, and kidney cancer. Koh et al found that PD1 is associated with poor prognosis in patients with classical Hodgkin's lymphoma, and that lowering the expression level of PD1 can improve overall survival. RS (Reed-Sternberg) cells are characteristic cells of Hodgkin's lymphoma with a high surface expressing PD-L1. When PD-L1 overexpressed on RS cells binds to the corresponding receptor PD1, it can inhibit the proliferation and activation of T cells, promote the growth of RS cells, and produce metastases.

Circulating tumor cells (CTC) are an important predictor of immunological checkpoint blockade therapy. The study found that CTC mediates the distant metastasis of tumor cells by regulating the expression level of PD-L1, and the transfer and tumor formation ability of CTC circulating colonies is 23 to 50 times that of single CTC. The study found that 11 (68.6%) of 16 patients with metastatic breast cancer with CTC had high expression of PD-L1. It is suggested that CTC can be regulated by targeted intervention of PD-L1 to reduce metastasis and recurrence of breast cancer.

Both PD1 and Treg cells are involved in distant metastasis and recurrence of tumors, and high levels of PD1 can enhance the inhibitory function of Treg cells. Some lymphocyte chemokines such as CCL2, CXCR2, and CXCL5 can increase the expression level of PD-L1, induce the occurrence of EMT, and promote the invasion and metastasis of cancer. Blocking the expression of CXCR2 can increase the sensitivity of PD1 antibody to immunotherapy, increase the infiltration of CD3+ T cells in tumor tissues and the activity of CD4+ and CD8+ T cells, and inhibit tumor invasion and metastasis.

PD1/PD-L1 Antibody in Tumor Immunotherapy

Nivolumab, a monoclonal antibody against PD1, restores the activity of T cells against tumor immune responses. In 2017, Bristol-Myers Squibb (BMS) announced the latest data on Nivolumab's single-agent use in 214 patients with advanced liver cancer. 43 patients had tumor shrinkage of at least 30% and objective efficiency increased to 20%; 64 patients had stable tumors. The disease control rate is as high as 64%; the September survival rate is 74%; the 3~4 grade adverse reaction rate is 20%. The latest phase III clinical trial results show for the first time that Nivolumab can significantly prolong the survival of patients with advanced gastric cancer.

Pembrolizumab is the first humanized PD1 monoclonal antibody marketed in the United States as a second-line drug for the treatment of melanoma. Goldberg et al. enrolled 52 patients with melanoma brain metastasis with positive PD-L1 expression and patients with non-small cell lung cancer with brain metastasis. The results showed that the objective response rate of patients with melanoma brain metastases was 22%, non-small cell lung cancer. The objective response rate of patients with brain metastases was 33%.

Atezolizumab is the first FDA-approved anti-PD-L1 immunotherapeutic for immunotherapy of bladder cancer and metastatic non-small cell lung cancer. In a Phase II clinical trial of cisplatin-treated late or metastatic urothelial cancer, the results showed that Atezolizumab treatment reduced tumor volume in 15% of patients. In patients with high PD-L1 expression, Atezolizumab treatment reduced tumor volume in 26% of patients. This indicates that the higher the level of PD-L1 expression in the patient's tumor, the greater the degree of remission achieved.

References:

(2017). Atezolizumab (tecentriq) for bladder cancer and nsclc. Medical Letter on Drugs & Therapeutics, 59(1515), e40.
Trojan, J. , & Sarrazin, C. . (2016). Complete response of hepatocellular carcinoma in a patient with end-stage liver disease treated with nivolumab: whishful thinking or possible|[quest]|. American Journal of Gastroenterology, 111(8), 1208.
Goldberg, S. B. , Gettinger, S. N. , Mahajan, A. , Chiang, A. C. , Herbst, R. S. , & Sznol, M. , et al. (2016). A phase ii trial of pembrolizumab for patients with melanoma or non-small cell lung cancer and untreated brain metastases. Lancet Oncology,17(7), 976.
Wang, X. , Sun, Q. , Liu, Q. , Wang, C. , Yao, R. , & Wang, Y. . (2016). Ctc immune escape mediated by pd-l1. Medical Hypotheses, 93, 138-139.
Koh, Y. W. , Jeon, Y. K. , Yoon, D. H. , Suh, C. , & Huh, J. . (2016). Programmed death 1 expression in the peritumoral microenvironment is associated with a poorer prognosis in classical hodgkin lymphoma. Tumor Biology, 37(6), 7507-7514.
Kankana, B. , Theodora, A. , & Boussiotis, V. A. . (2016). The pd1:pd-l1/2 pathway from discovery to clinical implementation. Frontiers in Immunology, 7.

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