Among all cancers, gastrointestinal (GI) cancers represent one of the leading public health issues worldwide and are responsible for 4.5 million global deaths per year, according to data from 2013. According to American Cancer Society (ACS) statistics, GI cancers collectively have the highest incidence and account for around 20% of estimated new cancer cases. They are the second leading cause of cancer deaths after lung cancer in the United States and are an increasing healthcare burden in many countries.

Since immune checkpoint inhibitors were first reported in 2010 and 2012, they have translated into a significant overall survival advantage in comparison to established therapies in metastatic melanomas and non-small-cell lung cancer (NSCLC). This success means their role is currently being evaluated in many GI cancers. Given the background of chronic inflammation in the pathogenesis of many GI cancers, the use of immune-based treatment approaches in such cancers might have a role in releasing the brakes created by the tumor on the immune system and in harnessing an immune response to effectively kill tumor cells. In addition, one of the mechanisms through which some GI cancers acquire radio-resistance is programmed-death ligand-1 (PD-L1) upregulation. The PD-L1/programmed-death-1 (PD-1) axis then induces T cell exhaustion and results in tumor escape from the host immune response. In order to overcome limitations created by the PD-L1/PD-1 interaction and to reduce the rate of tumor recurrence in these tumors, an immune-based treatment approach targeting PD-L1 and cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) may be beneficial.

In GI cancers, one of the leading causes of hypermutation is a defect in the DNA mismatch repair (MMR) system, which results in high microsatellite instability (MSI-H). MSI-H tumors strongly express various immunological checkpoint proteins, such as CTLA-4, PD-1, PD-L1, LAG-3, and IDO, which prevent elimination of neoplastic cells by counteracting the active immune microenvironment of the MSI-H tumor. As such, the use of anti-PD-1 therapy in colorectal cancer patients with MMR deficiency has recently been shown to have excellent outcomes. In fact, it has been linked to significantly better progression-free and overall survival in patients with MSI-H tumors when compared to those with microsatellite stable (MSS) tumors. This highlights the clinical significance of identifying the MSI status and hypermutated phenotype as a predictive marker for immuno-modulating agents.

This special issue will focus on whether the use of immunotherapy in GI cancers might have dramatic clinical responses similar to those obtained in other cancers. Authors are invited to contribute original research articles as well as review articles. This special issue particularly welcomes articles that offer an overview of the existing concepts, novel findings, controversies, and challenges in this area. Articles on future prospects of immunotherapy are also invited.

Potential topics include but are not limited to the following:

• Immunotherapy in esophageal cancer
• Immunotherapy in gastric cancer
• Immunotherapy in colorectal cancer
• Immunotherapy in pancreatic cancer
• Immunotherapy in cholangiocarcinoma
• Cost-effectiveness analyses of immunotherapy in GI cancers
• New or unexpected reports of toxicity from use of immunotherapy in GI cancers
• Quality of life of GI cancer patients on immunotherapy
• Immunotherapy in combination with systemic and/or radiation therapy in GI cancers