Immune inflammation indicators and implication for immune modulation strategies in advanced hepatocellular carcinoma patients receiving sorafenib

We evalueted a systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) with the aim to explored their prognostic value in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. 56 advanced HCC patients receiving sorafenib were available for our analysis. Lymphocyte, neutrophil and platelet were measured before beginning of treatment and after one month. Patient with SII ≥ 360 showed lower median PFS (2.6 vs. 3.9 months, P < 0.026) and OS (5.6 vs. 13.9 months, P = 0.027) with respect to patients with SII < 360. NLR ≥ 3 had a lower median PFS (2.6 vs. 3.3 months, P < 0.049) but not OS (5.6 vs. 13.9 months, P = 0.062) than those with NLR < 3. After adjusting for clinical covariates SII and NLR remained an independent prognostic factor for OS. The SII and NLR represent potential prognostic indicator in patients with advanced HCC treated with sorafenib.


INTRODUCTION
Hepatocellular carcinoma (HCC) represents the most common primary liver cancer with an increasing incidence [1].
The introduction of Sorafenib, currently representing the standard of care of advanced HCC, changed the clinical landscape even if a large proportion of patients show a limited efficacy with respect to toxic effects [2,3,4,5,6,7]. Until now predictive biomarkers of sorafenib Research Paper www.impactjournals.com/oncotarget efficacy or resistance have yet to be identified [8,9,10,11,12,13]. Systemic inflammatory responses have been shown to reflect the promotion of angiogenesis, DNA damage and tumor invasion through up-regulation of cytokines [14]. Previous research revealed that lymphocytes play a crucial role in tumor defense by inducing cytotoxic cell death and inhibiting tumor cell proliferation and migration [15]. In consideration of these factors, several inflammation and immune-based prognostic scores, such as lymphocyte count, neutrophil-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII), have been developed to predict survival and recurrence in cancers, including HCC [16,17].
Cancer immunotherapy has made huge progress in the last few years. In particular, recent studies focalize the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a genuine challenge for conventional immunotherapy in patients with HCC [18].
Herein, we evaluated the potential role of SII, NLR and PLR as predictors of outcome in HCC patients treated with sorafenib.

Patient characteristics
56 patients diagnosed with HCC were consecutively treated with sorafenib. The patients caracteristics and clinical outcome show in Table 1.
NLR and PLR modifications during the course of treatment show in Table 3.
The counts for neutrophils, lymphocytes and platelets alone without the ratio and clinical outcome show in Table 4.

OS
No.

DISCUSSION
In the present study, SII and NLR was show to be an indipendent predictor of OS for patients with HCC treated with sorafenib. Our results suggest that the SII could be a more objective marker that reflects the balance between host inflammatory and immune response status than indexes such as the PLR and NLR. In addition, our data have shown that a high SII basal and a month is associated with a worse prognosis respect other patients.
In neoplastic process, inflammatory cells are powerful tumor promoters; they produce an attractive environment for tumor growth, facilitating genomic instability and promoting angiogenesis [19]. Tumors are often infiltrated by various numbers of lymphocytes, macrophages and mast cells. It has been suggested that lymphocytes play central roles in host antitumor immune responses. Mouse models have shown that lymphocytes may control cancer outcome [20].
As an integrated indicator based on peripheral lymphocyte, neutrophil, and platelet counts, the predictive value of SII for cancer outcomes might be due to the function of these three types of cells. Lymphocytes and platelets have been proven to promote tumor development. In addition, recent evidence indicates that neutrophils enhance cancer cell invasion, proliferation, and metastasis and assist cancer cells with evading immune surveillance.
Several studies have shown that platelets induces circulating tumor cell epithelial-mesenchymal transition and promotes extravasation to metastatic sites [21,22]. Neutrophils promote adhesion and seeding of distant organ sites through the secretion of circulating growth factors such as vascular endothelial growth factor (VEGF) and proteases [23,24]. Lymphocytes play a crucial role in tumor defense by inducing cytotoxic cell death and inhibiting tumor cell proliferation and migration, thereby   SII, systemic immune-inflammation index; NLR, neutrophil-to.lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease dictating the host's immune response to malignancy [25]. Thus, inflammation induces changes in the cancer microenvironment changes that favor cancer progression. Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. Recent works on melanoma have shown thatb derived neutrophil-to-lymphocyte ratio may be associated with response to these drugs [26,27]. For this reason, our work highlights the possible benefit of a subset of patients with advanced hepatocellular carcinoma to treatment with ipilimumab. In conclusion the low cost, easy determination, and reproducibility of a full blood count make SII and NLR a promising tool for assessing HCC prognosis in future clinical practice.

Patient population
This retrospective study was conducted on 56 HCC patients consecutively treated at our institute (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori) from 2012 to 2015.
We enrolled only patients receiving oral treatment with either 400 mg of sorafenib (consisting of 2 200mg tablets) twice daily. Treatment with sorafenib was continued until disease progression, unacceptable toxicity or death occurred. Disease progression was assessed using Modified Response Evaluation Criteria in Solid Tumors (mRECIST).

Statistical analysis
The aim of this analysis was to examine the association between baseline SII, NLR and PLR levels and Progression-Free Survival (PFS) and Overall Survival (OS) in patients with HCC treated with sorafenib.
Information on neutrophil, lymphocyte and platelet counts from hematologic blood tests carried out at baseline (the day before the start of treatment) and one month was collected. Complete blood counts have been carried out with XE-2100 (Sysmex, Kobe, Japan).
The SII was calculated as platelet count × neutrophil count/lymphocyte count, NLR was obtained by dividing the absolute neutrophil count by the absolute lymphocyte count, and the PLR was calculated by as the ratio of the absolute platelet count to the absolute lymphocyte count.
Association between categorical variables was assessed using the Fisher's exact test, when appropriate.
PFS was defined as the time interval between the day of start of treatment and the day of documented disease progression, last follow-up visit if there was no progression or the day of death. OS was defined as the time interval between the day of start of treatment until the day of death or last follow-up visit. PFS and OS were estimated by the Kaplan-Meier method and curves were compared by the log-rank test. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics (age, gender, etiology, ECOG performance status) were calculated using the Cox proportional hazards model.
We also conducted landmark analyses to reduce possible confounding by time on treatment by assessing the impact of change in SII; NLR and PLR at 1 month landmark time on survival outcomes. X-tile 3.6.1 software (Yale University, New Haven, CT) was used to determine the cutoff value for baseline levels of each II. SII ≥360, NLR ≥3 and PLR ≥15 were considered as elevated levels.
All p values were based on two-sided testing and statistical analyses were performed using SAS statistical software version 9.4 (SAS Inc., Cary, NC, USA).