Cancer is a chronic disease whose mechanism of emergence and advancement is still mysterious to many scientists. There are multiple rationales for the development of the disease such as epigenetic factors, living habits, mutations in the gene, an impaired host immune system and many more.
1 Hence, cancer is the abnormal proliferation 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 stated by Hanahan Douglas and Robert A Weinberg 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 metastasis of cancer and evasion 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 metastasis is the concept of circulating cancer cell free chromatin. When the cancer patients undergo chemotherapy or radiation, a vast number of cells die.
From the dead cell, the chromatin fragments are realised into circulation and these fragments can thereby, integrate into the normal DNA of other cells causing metastasis of cancer. 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 production is highly regulated to avoid damage to the host and this is overlooked by immune checkpoints eminently by Programmed Death 1 (PD1). 7 Cancer cells use the host immune tolerance checkpoint to baffle the immune system by inhibiting PD1 and thereby, exhausting the T cells eventually leading to the growth and development of cancer. PD1 is present 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 yet no relationship has been deduced 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 PDL1 on tumour cell it results in the T cell 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 caused and modulated by cancer cell free chromatin.
Future, the proposal aims to inhibit cancer cfCh and analyse the expression of PD1.