Chemotherapy to reverse diminished immune responses (IRs) associated with a raised neutrophil lymphocyte ratio (NLR) in patients with advanced colorectal cancer (aCRC).

Background: High peripheral blood NLR is a poor prognostic marker in cancer patients. We investigated the relationship between NLR and measured IRs in patients with chemo-naïve aCRC and the modulation of both by chemotherapy. Methods: We characterised functional IRs of peripheral blood mononuclear cells of 29 aCRC patients undergoing first-line chemotherapy. Samples were collected prior to and after 6 weeks of chemotherapy. NLR of ≥5 was defined as high; < 5 as low. Innate immune function was determined by NK cell degranulation and cytotoxicity against target tumour cells; adaptive T cell responses against immune stimuli by IFN-γ ELISpot. Secretion of immunomodulatory cytokines was determined by Luminex assay and immune cell activation by flow cytometry. Results: 41% of patients had NLR ≥5 at baseline. High baseline NLR was associated with reduced overall survival (6.6 vs 18.8 months, p = 0.0024), diminished NK cell activity and increased levels of immune inhibitory cytokines TGF-β and IL-10 (p = 0.0004 and p = 0.0014) compared to a low baseline NLR. After 6 weeks of chemotherapy NLR normalised in 83% of patients with high NLR at baseline. In these patients functional analysis demonstrated enhanced immune responses compared to the group with low baseline NLR: NK cell degranulation and cytotoxicity increased (p = 0.004 and p = 0.02, respectively) and levels of TGF-β fell. Differences between the high and low NLR groups remained despite enhancement of IRs in the high NLR group following chemotherapy. T cell responses increased in both groups but patients with a low NLR demonstrated increased tumour-specific responses against carcinoembryonic antigen (CEA) compared to those with a high baseline NLR. Similarly, levels of IL-10 remained increased in the high NLR group despite normalisation of NLR. PD-1 expression increased on NK cells (p = 0.01), B cells (p = p = 0.04) and monocytes (p = 0.02). Conclusions: High NLR is associated with decreased survival in patients with aCRC. This may be due to diminished IRs, which can be improved/reversed following chemotherapy and could identify a group of patients in whom immunotherapies may be of benefit.