Predictive Biomarkers of Immune Checkpoint Inhibition in Gastroesophageal Cancers

Abstract

Immune checkpoint inhibition has transformed cancer treatment. For gastroesophageal cancer, this class of drugs have demonstrated durable responses and survival benefit in a subgroup of patients, resulting in regulatory approval. However, several recent randomized phase III studies in gastroesophageal cancer have reported negative results, blunting initial enthusiasm. Identification and validation of predictive biomarkers with appropriate patient selection for benefit from immunotherapy is an area of intense research with novel concepts rapidly emerging. In this review we describe the latest immune checkpoint inhibitor trials which have been reported in gastroesophageal cancers with a focus on predictive biomarkers. We also explore novel biomarkers being developed to improve precision oncology for immunotherapy in gastroesophageal cancers.

Keywords: biomarker; esophageal cancer; gastric cancer; gastroesophageal cancer; immune checkpoint inhibition; immunotherapy; precision oncology; predictive biomarker.

Figure 1

Multiplex immunohistochemistry/ immunofluorescence (mIHC/IF) staining of gastric carcinoma. Two gastric cancer samples are labeled with PD-L1 (Clone 22C3) (red), EpCAM (green), and DAPI (blue) by using mIHC/IF. EpCAM is a cell surface protein commonly expressed in gastric cancer cells. DAPI is a nuclear counterstain. (A–C) PD-L1 staining (in red) can be observed only on the immune cells surrounding the tumor nests. There is minimal PD-L1 expression within the tumor cells. Image A is mIHC/IF imaging of PD-L1 + DAPI, Image B is EpCAM + DAPI and Image C is PD-L1 + EpCAM + DAPI. (D–F) PD-L1 staining (in red) can be seen in both tumor compartment (majority of the positive cells are located in the yellow highlighted box) and surrounding immune cells. Image D is mIHC/IF imaging of PD-L1 + DAPI, Image E is EpCAM + DAPI and Image F is PD-L1 + EpCAM + DAPI. These images highlight the importance of considering immune-cell expression along with tumor expression of PD-L1 IHC, and the differences between TPS and CPS scores in gastric cancer. Representative images are shown with HALO^TM pathology analysis software. (Magnification: 200X).

Figure 2

Biomarkers of Immune Checkpoint Inhibition in Gastroesophageal Cancers. PD-L1 expression can be measured in the form of Combined Positive Score (CPS) has been shown to predict response to anti-PD1 or anti-PD-L1 therapies (1). Microsatellite Instability (MSI) leads to a large number of somatic mutations and production of neoantigens. MSI is one of the most common causes of high Tumor Mutational Burden (TMB) (2). EBV associated Gastric Cancer (EBVaGC) has been postulated to be sensitive to ICI due to high intra-tumoral immune infiltration and expression of PD-L1 and PD-L2 (3). Various gene signatures have been developed to identify genes that can predict response to ICI (4). Combination of HER-2 and anti-PD1 therapy enhance antibody-dependent cellular cytotoxicity leading to improved outcomes with ICI (5).