Study of immunosenescence in the occurrence and immunotherapy of gastrointestinal malignancies

Abstract

In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.

Keywords: Advanced gastric cancer; Cancer vaccines; Checkpoint inhibitors; Immunotherapy; Programmed death ligand-1 (PD-1) inhibitors.