Dataset Information

Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma.

ABSTRACT: The poor treatment response of oesophageal adenocarcinoma (OAC) leads to low survival rates. Its increasing incidence makes finding more effective treatment a priority. Recent treatment improvements can be attributed to the inclusion of the tumour microenvironment (TME) and immune infiltrates in treatment decisions. OAC TME is largely immunosuppressed and reflects treatment resistance as patients with inflamed TME have better outcomes. Priming the tumour with the appropriate neoadjuvant chemoradiotherapy treatment could lead to higher immune infiltrations and higher expression of immune checkpoints, such as PD-1/PDL-1, CTLA4 or emerging new targets: LAG-3, TIM-3, TIGIT or ICOS. Multiple trials support the addition of immune checkpoint inhibitors to the current standard of care. However, results vary, supporting the need for better response biomarkers based on TME composition. This review explores what is known about OAC TME, the clinical significance of the various cell populations infiltrating it and the emerging therapeutical combination with a focus on immune checkpoints inhibitors.

SUBMITTER: Belle CJ

PROVIDER: S-EPMC10753779 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma.

Belle Clemence J CJ Lonie James M JM Brosda Sandra S Barbour Andrew P AP

Frontiers in immunology 20231213

The poor treatment response of oesophageal adenocarcinoma (OAC) leads to low survival rates. Its increasing incidence makes finding more effective treatment a priority. Recent treatment improvements can be attributed to the inclusion of the tumour microenvironment (TME) and immune infiltrates in treatment decisions. OAC TME is largely immunosuppressed and reflects treatment resistance as patients with inflamed TME have better outcomes. Priming the tumour with the appropriate neoadjuvant chemorad ...[more]

PMID: 38155973

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Project description:A plateau in treatment effect can be seen for the current 'one-size-fits-all' approach to oesophageal adenocarcinoma (OAC) management using neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT). In OAC, the tumour microenvironment (TME) is largely immunosuppressed, however a subgroup of patients with an immune-inflamed TME exist and show improved outcomes. We aimed to understand the overall immune-based mechanisms underlying treatment responses and patient outcomes in OAC, and in relation to neoadjuvant therapy modality. This study included 107 patients; 68 patients were enrolled in the Australian Gastro-Intestinal Trials Group sponsored DOCTOR Trial, and 38 patients were included from the Cancer Evolution Biobank. Matched pre-treatment and post-treatment tumour biopsies were used to perform multi-modality analysis of the OAC TME including NanoString mRNA expression analysis, multiplex and single colour immunohistochemistry (IHC), and peripheral blood mononuclear cell analysis of tumour-antigen specific T cell responses. Patients with the best clinicopathological outcomes and survival had an immune-inflamed TME enriched with anti-tumour immune cells and pathways. Those with the worst survival showed a myeloid T regulatory cell enriched TME, with decreased CD8+ cell infiltration and increased pro-tumour immune cells. Multiplex IHC analysis identified that high intra-tumoural infiltration of CD8+ cells, and low infiltration with CD163+ cells was associated with improved survival. High tumour core CD8+ T cell infiltration, and a low tumour margin infiltration of CD163+ cells was also associated with improved survival. nCRT showed improved survival compared with nCT for patients with low CD8+, or high CD163+ cell infiltration. Poly-functional T cell responses were seen with tumour-antigen specific T cells. Overall, our study supports the development of personalised therapeutic approaches based on the immune microenvironment in OAC. Patients with an immune-inflamed TME show favourable outcomes regardless of treatment modality. However, in those with an immunosuppressed TME with CD163+ cell infiltration, treatment with nCRT can improve outcomes. Our findings support previous studies into the TME of OAC and with more research, immune based biomarker selection of treatment modality may lead in improved outcomes in this deadly disease.

Project description:Objectives2-deoxy-2[18F]Fluoro-D-glucose (FDG) PET-CT has an emerging role in assessing response to neoadjuvant therapy in oesophageal cancer. This study evaluated FDG PET-CT in predicting pathological tumour response (pTR), pathological nodal response (pNR) and survival.MethodsCohort study of 75 patients with oesophageal or oesophago-gastric junction (GOJ) adenocarcinoma treated with neoadjuvant chemotherapy then surgery at Guy's and St Thomas' NHS Foundation Trust, London (2017-2020). Standardised uptake value (SUV) metrics on pre- and post-treatment FDG PET-CT in the primary tumour (mTR) and loco-regional lymph nodes (mNR) were derived. Optimum SUVmax thresholds for predicting pathological response were identified using receiver operating characteristic analysis. Predictive accuracy was compared to PERCIST (30% SUVmax reduction) and MUNICON (35%) criteria. Survival was assessed using Cox regression.ResultsOptimum tumour SUVmax decrease for predicting pTR was 51.2%. A 50% cut-off predicted pTR with 73.5% sensitivity, 69.2% specificity and greater accuracy than PERCIST or MUNICON (area under the curve [AUC] 0.714, PERCIST 0.631, MUNICON 0.659). Using a 30% SUVmax threshold, mNR predicted pNR with high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%, p = 0.010). pTR, mTR, pNR and mNR were independent predictive factors for survival (pTR hazard ratio [HR] 0.10 95% confidence interval [CI] 0.03-0.34; mTR HR 0.17 95% CI 0.06-0.48; pNR HR 0.17 95% CI 0.06-0.54; mNR HR 0.13 95% CI 0.02-0.66).ConclusionsMetabolic tumour and nodal response predicted pTR and pNR, respectively, in patients with oesophageal or GOJ adenocarcinoma. However, currently utilised response criteria may not be optimal. pTR, mTR, pNR and mNR were independent predictors of survival.Key points• FDG PET-CT has an emerging role in evaluating response to neoadjuvant therapy in patients with oesophageal cancer. • Prospective cohort study demonstrated that metabolic response in the primary tumour and lymph nodes was predictive of pathological response in a cohort of patients with adenocarcinoma of the oesophagus or oesophago-gastric junction treated with neoadjuvant chemotherapy followed by surgical resection. • Patients who demonstrated a response to neoadjuvant chemotherapy in the primary tumour or lymph nodes on FDG PET-CT demonstrated better survival and reduced rates of tumour recurrence.

Dataset Information

Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma.

Publications

Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma.

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