RESUMO
Background and purpose: PD-1 and PD-L1 are involved in anticancer immunosurveillance, and their expression may be predictive for therapeutic effectiveness of specific antibodies. Their influence on response to neoadjuvant radiochemotherapy (RCT) and prognosis in patients with oesophageal adenocarcinoma (OAC) remains to be defined. Materials and methods: Between 10/2004 and 06/2018, complete pre-RCT biopsy-specimens were available from 76 patients with locally advanced, non-metastatic OAC scheduled for trimodality therapy. We evaluated intra- and peritumoural expression of CD8, PD-1 and PD-L1 in pre-treatment specimens to determine their influence on tumour regression grade and survival. PD-1 and PD-L1 expression were considered positive (+) if ≥1% of all cells were stained positive, otherwise negative (-); densities of CD8+ cells were categorized as being high (Hi) or low (Lo) according to the median. Results: A negative PD-L1 expression in peritumoural cells predicted a poor tumour regression (RD 0.24 [95% CI 0.03-0.44], p = 0.023). A positive PD-1 expression in intra- as well as peritumoural cells was identified as an unfavourable prognostic factor (HR 0.52 [95% CI 0.29-0.93], p = 0.028; HR 0.50 [0.25-0.99], p = 0.047, respectively). With respect to CD8+ infiltration, positive PD-1 and PD-L1 expressions attenuated its favourable prognostic effect in intratumoural area (LoCD8/PD1 + vs. HiCD8/PD1-: HR 0.25 [0.09-0.69], p = 0.007; LoCD8/PDL1+ vs. HiCD8/PDL1-: HR 0.32 [0.12-0.89], p = 0.028) and were associated with negative outcome when seen in peritumoural area (HiCD8/PD1+ vs. LoCD8/PD1-: HR 0.29 [0.11-0.74], p = 0.010); HiCD8/PDL1+ vs. LoCD8/PDL1-: HR 0.33 [0.12-0.90], p = 0.031). Conclusions: PD-1 and PD-L1 expression were identified to be of predictive and prognostic value in patients with OAC, particularly when considering CD8+ infiltration. Further validation by a large size dataset is required.
RESUMO
BACKGROUND AND PURPOSE: Tumour infiltrating lymphocytes (TIL) and tumour associated macrophages (TAM) play a key role in anticancer immunosurveillance. We studied their influence on response to neoadjuvant radiochemotherapy (RCT) and prognosis in patients with oesophageal adenocarcinoma (OAC). MATERIALS AND METHODS: Between 10/2004 and 06/2018, pre-RCT biopsy-specimens were available from 76 patients with locally advanced, non-metastatic OAC scheduled for trimodality therapy. We evaluated intra- and peritumoural expression of FoxP3+-, CD8+-TIL and CD68+-, CD163+-TAM, contemplating cell density, cell ratios and cell-to-cell distances to determine a possible influence on tumour regression grade (TRG) and survival. Median follow-up time for all patients was 18 months (IQR 9-43), and 54 months (25-97) for surviving patients. Data were analysed using risk analysis, logrank test and Cox regression. RESULTS: Poor tumour regression was detected for cN+ (RR 0.77 [95% CI 0.66-0.90], p = 0.001), low intratumoural FoxP3+/CD8+ ratio (RR 0.75 [0.60-0.96], p = 0.020), high peritumoural CD163+/CD68+ ratio (RR 0.77 [0.60-0.99], p = 0.045) and high intratumoural TAM density (RD -0.44 [-0.82 to -0.06], p = 0.023). Apart from poor resection quality and TRG, pretherapeutic high peritumoural CD8+ infiltration (HR 2.36 [1.21-4.61], p = 0.012) and short intratumoural FoxP3+ to CD8+ cell-to-cell distances in middle ranged CD8+ density (HR 2.55 [1.00-6.52], p = 0.050) were significant unfavourable prognostic factors in multivariate analysis. CONCLUSIONS: Immunologic parameters, such as CD8+-, FoxP3+-TIL and CD68+-, CD163+-TAM, were identified to be of independent predictive and prognostic value in patients with OAC. Further and independent validation of these biomarkers by a large size dataset may urgently be contemplated.
