The Cancer-Immune Set Point in Oesophageal Cancer

Abstract

Immunotherapy has achieved long-term disease control in a proportion of cancer patients, but determinants of clinical benefit remain unclear. A greater understanding of antitumor immunity on an individual basis is needed to facilitate a precision oncology approach. A conceptual framework called the "cancer-immune set point" has been proposed to describe the equilibrium between factors that promote or suppress anticancer immunity and can serve as a basis to understand the variability in clinical response to immune checkpoint blockade. Oesophageal cancer has a high mutational burden, develops from pre-existing chronic inflammatory lesions and is therefore anticipated to be sensitive to immune checkpoint inhibition. However, both tumour- and patient-specific factors including the immune microenvironment, the microbiome, obesity, and host genetics contribute to an immune set point that confers a lower-than-expected response to checkpoint blockade. Immunotherapy is therefore currently confined to latter lines of treatment of advanced disease, with no reliable predictive biomarker of response. In this review, we examine oesophageal cancer in the context of the cancer-immune set point, discuss factors that contribute to response to immunotherapeutic intervention, and propose areas requiring further investigation to improve treatment response.

Keywords: cancer immunology; immune checkpoint inhibitors; immunotherapy; oesophageal cancer; prognostic markers.

Figure 1

Immune checkpoints and therapeutic targets in the anti-tumour immune response. Cytotoxic T lymphocyte antigen 4 (CTLA4) is a ligand expressed by T cells which prevents T cell activation and can be blocked by Ipilimumab (anti CTLA4). Activated T cells express programmed cell death protein 1 (PD1) which transmits an inhibitory signal that attenuates cytolytic activity when bound to programmed death ligand 1 (PDL1). Monoclonal antibodies that interfere with the PD1/PDL1 interaction (anti PDL1; anti PD1) allow re-invigoration of T cells.

Figure 2

Immunological progression in the malignant transformation to oesophageal adenocarcinoma (OAC). Reflux oesophagitis is accompanied by a TH₁ pattern of inflammation which shifts to a TH₂ pattern in Barrett's oesophagus. Malignant transformation is marked by a mixed TH₁/TH₂ pattern with tolerogenic dendritic cells (DCs), regulatory T (Treg) cells, myeloid derived suppressor cells (MDSCs).

Figure 3

The tumour microenvironment (TME) in oesophageal adenocarcinoma. The presence of M2-polarised tumour-associated-macrophages (TAM), regulatory T cells (Treg), and myeloid derived suppressor cells (MDSCs) restrict the action of cytotoxic CD8⁺ T cells (CD8 T cells), natural killer (NK) cells, and mucosa associated invariant T (MAIT) cells. Cancer associated fibroblasts (CAFs) and adipocytes derived stem cells (ADSCs) secrete extracellular matrix (ECM) and prevent migration of effector T cells to the tumour parenchyma.