Prognostic Significance of the Neutrophil/Lymphocyte Ratio in Patients undergoing Treatment with Nivolumab for Recurrent Non-Small-Cell Lung Cancer

Abstract

Aim: We investigated the prognostic potential of pretherapy measurement of the neutrophil/lymphocyte ratio (NLR) in patients (n = 56) with non-small-cell lung cancer deemed suitable for treatment with nivolumab. Materials & methods: This was a multicenter, noninterventional, retrospective data analysis, involving five oncology centers. Results: Patients with prenivolumab NLR values of <5 and ≥5 had respective median overall survival (OS) values of 14.5 and 7.02 months (p = 0.0026). Patients with ≤2 and >2 metastatic sites had median OS values of 11.4 and 6.1 months, respectively (p = 0.0174). A Cox multiple regression model revealed baseline NLR ≥5 as the only variable significantly associated with decreased OS (p < 0.0447). Conclusion: Pretreatment elevated NLR values are associated with poor outcomes in patients with recurrent metastatic non-small-cell lung cancer treated with nivolumab.

Frontiers in Pharmacology: Review Manuscript Targeting of the Neutrophil as an Adjunctive Strategy in Non-Small Cell Lung Cancer

“…Much of the evidence implicating neutrophils in the pathogenesis of both progression of NSCLC and attenuation of treatment efficacy, has been derived from routine hematological investigations. These include enumeration of the number of circulating neutrophils and lymphocytes ( Schernberg et al, 2018 ; Rapoport et al, 2020 ) and using this data to calculate the NLR by dividing the total number of neutrophils by the total lymphocyte count. Although awaiting validation, a resultant NLR most commonly of ≥5 (although some studies use lower cut-off values of 3 or 4) is indicative of subclinical systemic inflammation and immunosuppression.…”

“…Accumulation of systemic and intratumoral neutrophils has been associated with higher tumor progression in experimental models ( Schernberg et al, 2018 ; Pfirschke et al, 2020 ; Rapoport et al, 2020 ) and poor prognosis in patients ( Kargl et al, 2019 ). Concordantly, soluble factors that increase bone marrow exit and tumor recruitment of PMN cells correlate with therapy resistance and tumor malignancy.…”

“…As mentioned above, however, only those that are most recent and seemingly innovative and promising in the setting of NSCLC, in our opinion, are covered in detail here. In addition to ROS, NO, TGF-β1 and IL-10, other putative neutrophil/MDSC-derived immunosuppressive mechanisms that have been reviewed elsewhere include: 1) depriving T cells in the TME of arginine, tryptophan and cysteine via release of arginase1, indoleamine 2,3-dioxygenase and sequestration of cystine, respectively ( Srivastava et al, 2010 ; Yu et al, 2013b ; Treffers et al, 2016 ; Groth et al, 2019 ); and 2) release of adenosine that promotes intracellular production of immunosuppressive 3′,5′-cyclic adenosine monophosphate ( Groth et al, 2019 ; Rapoport et al, 2020 ).…”

“…Measured prior to and during anticancer therapy, this, in turn, has been reported in numerous studies (too numerous to be listed here), to be associated with a negative clinical outcome and poor responsiveness to various types of anti-cancer treatments. These include chemotherapy, radiotherapy and surgery (Sarraf et al, 2009;Tomita al., 2011;Peng et al, 2015;Scilla et al, 2017;Mizuguchi et al, 2018;Doi et al, 2019), and, more recently, inhibitory immune checkpointtargeted therapies (Banna et al, 2020;Huang and Shen, 2020;Jin et al, 2020;Rapoport et al, 2020b). Although of particular relevance to NSCLC, the prognostic value of the NLR has also been described in many other common malignancies (Donskov, 2013;Howard et al, 2019).…”

SiglecFhigh neutrophils in lung tumor tissues suppress local CD8 T cell responses and limit the efficacy of anti PD-L1 antibodies

“…In lung cancer, a high neu to lymphocyte ratio in peripheral blood is a wellestablished negative prognostic marker and neu density in tumor tissues has been associated to worst disease outcome (13)(14)(15). More recently, an abundant neu infiltrate has been associated to limited efficacy of checkpoint inhibitors in various cancers, including lung cancer (16)(17)(18) and neu density in tumor tissues was directly linked to decreased local antitumoral CD8 responses (19). Single cell sequencing and mass-cytometry has begun to unravel the diversity and complexity of neu subsets in tumor bearing hosts, underscoring the presence of different states with diverse tumor promoting potential and the importance to focus on neu infiltrating, non-ectopic, relevant tumor tissues (20)(21)(22).…”