Dynamics of blood neutrophil-related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non-small cell lung cancer: A hypothesis-generating study

Abstract

Several recent studies have shown that salvage chemotherapy following PD-1 blockade produces high antitumor activity in some patients with non-small lung cancer (NSCLC). However, the underlying synergistic mechanisms remain uncertain. The blood neutrophil-to-lymphocyte ratio (NLR) and absolute neutrophil count (ANC) can reflect the number of circulating myeloid-derived suppressor cells and tumor-associated neutrophils. The immunosuppressive status of the tumor microenvironment could be monitored by the time-series patterns of NLR and ANC. The dynamics of NLR and ANC during nivolumab treatment were retrospectively explored in 15 patients: 8 patients receiving subsequent salvage chemotherapy (2 groups: 3 non-responders and 5 responders), and 7 responders to nivolumab alone (2 groups: 4 partial response and 3 complete response). The dynamics of NLR and ANC during nivolumab differed among these four groups (NLR P = 0.045, ANC P = 0.067). NLR and ANC during nivolumab treatment increased over time in non-responders to salvage chemotherapy, with an inverse relationship between drug response and NLR or ANC at four to six weeks among the four groups. We hypothesize that the early dynamics of NLR and ANC during nivolumab may be associated with the late efficacy of subsequent salvage chemotherapy. Further studies involving a large cohort are needed to confirm these findings, which could provide insight into the role of myeloid immunosuppressor cells in combination PD-1 blockade and chemotherapy.

Keywords: Immune checkpoint inhibitor; neutrophil-to-lymphocyte ratio; salvage chemotherapy.

Figure 1

(a) The dynamics of the neutrophil‐to‐lymphocyte ratio (NLR) among the four groups: non‐responders and responders to salvage chemotherapy following nivolumab therapy, and patients with a partial response (PR) and a complete response (CR) to nivolumab alone. The vertical bars indicate standard errors. The dynamics of NLR are significantly different among the four groups (P = 0.045) () Non‐responders, () Responders, () Patients with PR, and () Patients with CR. (b) The dynamics of the absolute neutrophil count (ANC). The values of ANC were log‐transformed for normalization. The dynamics of log ANC over time show a similar trend (P = 0.067) () Non‐responders, () Responders, () Patients with PR, and () Patients with CR.

Figure 2

The relationships of drug response with the neutrophil‐to‐lymphocyte ratio (NLR) and the absolute neutrophil account (ANC) among the four groups: non‐responders and responders to salvage chemotherapy following nivolumab therapy, and patients with a partial response (PR) and a complete response (CR) to nivolumab alone. The vertical bars indicate standard errors. The values of ANC were log‐transformed for normalization. The relationships between drug‐response and the (a) six‐week NLR (P = 0.048) and six‐week ANC (P = 0.044) and (b) the four‐week NLR (P = 0.021) and four‐week ANC (P = 0.071) show a similar relationship. () NLR, and () ANC.

Figure 3

A hypothetical model of the possible underlying mechanisms of nivolumab and subsequent salvage chemotherapy, based on the results of our previous and present studies.4, 25, 28 PD‐1 expression levels on tumor‐infiltrating lymphocytes (TILs) probably indicate the exhaustion of lymphocytes. The dynamics of the neutrophil‐to‐lymphocyte ratio (NLR) and absolute neutrophil count (ANC) during nivolumab treatment possibly reflect the number of myeloid‐derived suppressor cells (MDSCs) and tumor‐associated neutrophils (TANs) in the tumor. These combinations may contribute to the efficacy of each therapy. Cx, chemotherapy.