br Impact of Adjuvant Chemotherapy on PD L Expression br
Impact of Adjuvant Chemotherapy on PD-L1 Expression
infection.4 Interaction of PD-L1 on the tumor AWD 131-138 with PD-1 on T-cells abrogates T-cell function and prevents the immune system from attacking the tumor cells, resulting in tumor cell proliferation and immune escape.5 However, blocking the interaction between PD-1 and PD-L1 enhances T-cell response and therefore antitumor activity.6 The PD-1 inhibitor pembrolizumab has been approved as first-line therapy for metastatic NSCLC with PD-L1 expression 50 % of the tumor cells and as second-line therapy in cases expressing > 1 % PD-L1.7,8 Yet, PD-L1 expression on tumor cells and on immune cells is a dynamic process explaining the variability in PD-L1 expression and difficulty to predict response to check-point inhibitors.9 Patients with NSCLC with PD-L1 expression < 1 % are treated with platinum-based standard chemotherapy as first-line therapy. They covalently bind DNA and crosslink DNA stand, thus inhibiting DNA replication and transcription resulting in apoptosis.10 In the past, chemotherapies consisting mainly of cytotoxic drugs were thought to induce cell death without a major impact on the immune system. However, recent data describe a more comprehensive mode of action with immunomodulatory effects being part of the response. Platinum-based chemotherapies enhance the immune-stimulatory capacity of dendritic cells, inducing the infiltration of cytotoxic T-cell lymphocytes and the ablation of regulator T-cells and possibly upregulating major his-tocompatibility complex class I.11,12 These findings demonstrate that combination therapies might represent a novel therapeutic approach in NSCLC. The design of such combination therapies mandates a deeper understanding of the underlying biological processes. First results of combined standard platinum-based chemotherapy with the PD-1 inhibitor nivolumab have shown encouraging overall survival rates and acceptable tolerability.13
Nonetheless, the impact of standard platinum-based chemo-therapy on PD-L1 expression in patients with NSCLC remains controversial.14-17
The aim of this study was to investigate whether platinum-based chemotherapy might induce PD-L1 expression in the tumor tissue. In addition, we assessed whether genetic driver alterations correlate with PD-L1 expression.
Materials and Methods
We retrospectively collected and reviewed the medical records of patients with histologically confirmed NSCLC, who underwent surgical resection followed or not by adjuvant chemotherapy and presented NSCLC recurrence. Adjuvant chemotherapy was administrated according to tumor classification, including TNM status (TNM staging system). Specifically, clinical data were collected from 2007 until 2017 at University Hospital Zurich. For the defined patient cohort, we retrieved available tumor specimens to assess PD-L1 expression in both the initial tumor sample and NSCLC recurrence.
This study was approved by the local ethics committee (EK-ZH-2018-01919) and in accordance with the local laws and regulations.
Evaluation of PD-L1 Expression by IHC
We retrieved 72 pathologically confirmed primary lung cancer specimens from patients who underwent surgery and biopsy at NSCLC recurrence. For every case, all hematoxylin and
eosin-stained slides were reviewed for confirmation of diagnosis; one block was then selected for PD-L1 analysis. From each block, specimens were formalin-fixed, paraffin embedded, sectioned into 4-mm sections and stained for PD-L1 with a rabbit monoclonal antibody (clone E1L3N; Cell Signaling Technology, Danvers, MA).18,19 PD-L1 IHC was performed on all slides using Cell Signaling-E13LN monoclonal antibody. The IHC score was defined as the proportion of tumor cells with stained cell mem-branes. Migration of IHC group was considered as a significant change upon the PD-L1 expression. In order to evaluate change in the PD-L1 expression, 4 IHC score groups were created as defined in previous studies: TC0 < 1%, TC1 1% and < 5%, TC2 5% and < 50%, and TC3 50%.20,21 Scoring was performed inde-pendently by 2 pathologists (A.S. and D.S.).
Descriptive statistics were performed to evaluate patient and tu-mor characteristics. Difference in PD-L1 expression in the initial tumor sample and at NSCLC recurrence in the 2 groups (adjuvant and no adjuvant chemotherapy) was evaluated by the Pearson c2 test. Statistical analysis was performed with SPSS software, and a P value < .05 was considered as statistically significant.
A total of 36 patients were included in our study. All patients presented NSCLC recurrence after surgical resection with or without adjuvant chemotherapy (chemotherapy regimens are shown in Table 1) depending on the initial tumor classification (TNM staging system). Twenty (56%) patients underwent adjuvant chemotherapy after surgical resection. Sixteen (44%) patients had no adjuvant chemotherapy after surgical resection. All patients presented with the histologic type of adenocarcinoma. The median time to recurrence was 516 days for patients receiving adjuvant chemotherapy and 569 days for patients with no adjuvant chemotherapy.