Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to ICI

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Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors

Abstract

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.

Introduction

In recent years, immune checkpoint inhibitors (ICIs) targeting inhibitory receptors on T cells have achieved tumor responses in a subset of patients across a wide range of cancer types. However, most patients treated with ICI do not experience clinical benefit. This situation creates a need for biomarkers that would help clinicians identify those patients who are more likely to have extended survival and whose tumors are more likely to respond to ICI. This may help facilitate precise, cost-effective treatments with fewer adverse events.

There are several molecular and genomic biomarkers with predictive value for ICI across multiple cancer types. These include programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), mutations in specific genes, human leukocyte antigen class I zygosity and diversity, and microsatellite instability (MSI) status1,2,3,4,5,6,7. Within the tumor immune microenvironment, a higher degree of infiltration of myeloid cells and a lower level of infiltration of lymphocytes have each been associated with worse outcomes, including in patients treated with ICI8,9,10,11. However, these biomarkers have limitations that have precluded widespread clinical use, such as the need for sufficient tumor tissue, the need to sequence DNA extracted from tumor, and the lack of standardized quantitative scoring systems for immune cell or PD-L1 immunohistochemistry12,13. There is a clinical need for predictive biomarkers that can be easily obtained at low cost, in diverse (including resource-poor) settings, and without recourse to advanced genomic technologies or specialized histopathologic expertise. Candidates for cost-effective and accessible biomarkers include factors in peripheral blood.

In the context of cancer, work on immune-related markers in peripheral blood has focused on the neutrophil-to-lymphocyte ratio (NLR). This ratio, defined by the absolute counts of neutrophils and lymphocytes, may represent the balance between pro-tumoral inflammatory status and anti-tumoral immune response. An extensive body of research describes NLR as a general prognostic factor across several cancer types14,15,16,17,18,19,20. It is unknown, however, whether NLR is associated with prognosis in patients treated with ICI or has predictive value for the likelihood of response to ICI. Most studies examining this question have been performed either in small subsets of patients or in specific cancer types. The association of NLR with ICI response is not well understood21,22,23,24,25,26,27,28,29.

The aim of this retrospective cohort study is to analyze the association of pretreatment peripheral blood NLR with survival and response rates, in a large series of patients diagnosed with a wide range of cancer types treated with ICI. Secondarily, we analyze the predictive value of combining this clinical marker of host immunity (NLR) with a genomic marker of tumor antigenicity (TMB), by integrating tumor sequencing data.

In this work, we show that higher NLR is associated with poorer survival and a lower probability of response to immunotherapy, both at a pan-cancer level and within several cancer types. Moreover, combining NLR with TMB provides additional predictive value in patients treated with ICI.



https://www.nature.com/articles/s41467-021-20935-9