CD8+ tissue resident memory T lymphocytes and disease control in human oesophageal adenocarcinoma

Abstract

The development of novel treatments for oesophageal adenocarcinoma (OAC) represents an area of significant unmet need. Incidence has increased across western populations in recent decades, and despite improvements in oncological therapies and surgical techniques, 5 year survival remains at approximately 17%. Despite features suggesting potential response to treatment with immune checkpoint blockade, the benefits of such approaches in OAC have been modest.
A flow cytometric approach has been adopted to undertake immune phenotyping of human OAC specimens, obtained during curative resection, to assess factors related to lymphocyte dysfunction and exhaustion. It was observed that OAC are variously, but often highly, infiltrated with a population of antigen experienced CD8+ T lymphocytes (TILs) that express high levels of both PD-1 and CD39 and an abundance of this population was associated with improved progression free and overall survival. While a small sub population within this group express multiple exhaustion markers, these TILs do not appear to conform to the classical picture of lymphocyte exhaustion.
The dominant PD-1+ and CD39+ lymphocyte population was investigated utilising bulk RNA sequencing and flow cytometric based functional analysis. This has demonstrated a population dominated by precursor exhausted-like tissue resident memory CD8+ lymphocytes, identified through their transcriptomic profile as well as by their CD103+ and TIM3- phenotypes, and is consistent with TILs described as being associated with improved survival in various cancers. This population demonstrated a maintained proliferative potential, and an ability to degranulate and produce the key effector molecules IFN-γ, TNF-α and Granzyme B. The minority TIM3+ LAG3+ group among PD-1 and CD39 positive TILs corresponds to a terminally exhausted-like tissue resident memory CD8+ lymphocyte phenotype previously described as correlating with therapeutic response to immune checkpoint blockade, and the relative lack of this population in OAC points to a potential mechanism for the poor responses seen to immunotherapy.

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Identifiers

ORCID for Tim Elliott: orcid.org/0000-0003-1097-0222

ORCID for Timothy Underwood: orcid.org/0000-0001-9455-2188

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