Cancer Programmed Death 1 (PD1) to avoid damage

Cancer is a chronic disease whose emergence and advancement is still mysterious to many scientists. There are multiple rationales for the development of the disease such as epigenetic factors, mutations in the gene, an impaired host immune system and many more. 1 Hence, cancer is the irregular production of a cell caused due to epigenetics and genetic factors. 2 For the treatment of cancer, researchers have been focusing on the hallmarks of cancers. 3 The hallmarks of cancer are angiogenesis, enabling replicative immorality, sustaining signals for proliferation, deterring cell death, evading immune surveillance and triggering invasion and metastasis. 2 Presently, the focal point of numerous experiments is to understand two hallmarks: the spread of cancer from a primary site to other tissues and escaping of cancer cells from the immune surveillance. 3 Metastasis of cancer is accomplished due to various reasons including the genome metastasis hypothesis. Our laboratory is working on genome metastasis; the theory explains that cell free chromatin from cancer cells acts as a seeds for the formation of supportive metastatic niche formation into distant organs (soil). When the cancer patients undergo chemotherapy or radiation, a vast number of cells die. From the dead cell, the chromatin fragments are released into circulation and these fragments can thereby, integrate into the normal DNA of other cells inducing genome instability. 4 The immune system recognises the neoantigen formed by the cancer cells as foreign and elicit an immune response by triggering the T cells which eventually initiates the production of cytotoxic T lymphocytes (CTLs). 5 To induce an immunogenic response it is essential to have the co-stimulatory signals and coordination of CTLs. 56 Under normal physiology, T cells are constantly under the regulatory control by Tregs (CD4+, CD25+, FOXP3+) as a part of peripheral tolerance, including the checkpoints Programmed Death 1 (PD1) to avoid damage to the host. 7 Cancer cells antigens establish tolerance against the T cells MHC repertoire by exploiting the PD1 pathway for its own growth and development. PD1 is expressed on variety of immune cells including T cells, B cells, dendritic cells and tumour infiltrating lymphocytes. PD1 has two ligands, PDL1 and PDL2. PDL1 is present on tumour cells and antigen presenting cells. Its role in cancer is very prominent. There is minimal information on PDL2 and its relation to cancer. 8 PDL1 is produced on cancer cells due to its microenvironment, the over secretion of pro inflammatory cytokines of tumour necrosis factor alpha and interferon gamma. When PD1 on the immune cells bind to the PD-L1 on tumour cells, it results in the T cells exhaustion, conversion of naïve CD4+ T cells to Treg cells eventually diminishing immune response.910 The goal of this study is to therefore understand if PD1 expression is modulated by cancer cell free chromatin. Further, the proposal aims to inhibit cancer cfCh and attempt to reverse the anergic state of T cells.Rationale of the study supported by cited literatureFor the treatment of cancer, several immunotherapy approaches have been appraised and yet the results have not been promising. There are ranges of side- effects associated with immunotherapy against checkpoints inhibitors. These include gastrointestinal, dermatologic, endocrine and hepatic toxicity. 11 In addition, it also manifests lupus like autoimmune diseases in mouse model of C57 BL6 PD1-/-. 12 Therefore, the thrust of this study is to delineate the immune-cancer cross talks which can be targeted by pharmaceutical intervention as a therapy for cancer.  


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