Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 72, Issue 1, Pages 55-71Publisher
SPRINGER
DOI: 10.1007/s00262-022-03228-y
Keywords
A2aR; Acidosis; Lactate; Immune checkpoints; Oesophageal adenocarcinoma; Tie-2
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Tumour acidosis inhibits anti-tumour immunity and affects the profiles of T cells in oesophageal adenocarcinoma (OAC). Immune checkpoint blockade (ICB) can enhance anti-tumour T cell immunity under acidosis. Lactate is linked to metastasis.
Tumour acidosis contributes to cancer progression by inhibiting anti-tumour immunity. However, the effect of acidosis on anti-tumour T cell phenotypes in oesophageal adenocarcinoma (OAC) is unknown. Therefore, this study investigated the effect of acidosis on anti-tumour T cell profiles and if immune checkpoint blockade (ICB) could enhance anti-tumour T cell immunity under acidosis. Acidic conditions substantially altered immune checkpoint expression profiles of OAC patient-derived T cells, upregulating TIM-3, LAG-3 and CTLA-4. Severe acidosis (pH 5.5) significantly decreased the percentage of central memory CD4(+) T cells, an effect that was attenuated by ICB treatment. ICB increased T cell production of IFN-gamma under moderate acidosis (pH 6.6) but not severe acidosis (pH 5.5) and decreased IL-10 production by T cells under severe acidic conditions only. A link between lactate and metastasis was also depicted; patients with nodal metastasis had higher serum lactate levels (p = 0.07) which also positively correlated with circulating levels of pro-angiogenic factor Tie-2. Our findings establish that acidosis-induced upregulation of immune checkpoints on T cells may potentially contribute to immune evasion and disease progression in OAC. However, acidic conditions curtailed ICB efficacy, supporting a rationale for utilizing systemic oral buffers to neutralize tumour acidity to improve ICB efficacy. [GRAPHICS] .
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