Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

Abstract

Histamine (HDC) inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer (NK) and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). We have explored this potential mechanism clinically in two randomised phase II trials in metastatic renal cell carcinoma (mRCC). In parallel with the clinical trial in Denmark (n ¼ 63), we obtained serial blood samples and tumour biopsies searching for a potential histamine effect in situ. At baseline and on-treatment weeks 3 and 8, we monitored the 'good guys' (i.e. NK and T cells) and 'bad guys' (i.e. monocytes/macrophages and neutrophils) simultaneously in blood (n ¼ 59) and tumour tissue (n ¼ 44). Patients with high number of monocytes and neutrophils in peripheral blood had very poor survival, with apparently no benefit from either IL-2 alone or IL-2/HDC treatment. Blood monocytes (r ¼ À0.36, P ¼ 0.01) and neutrophils (r ¼ À0.46, P ¼ 0.001) were negatively correlated with cytotoxicity, whereas blood NK cells were positively correlated with cytotoxicity (r ¼ 0.39, P ¼ 0.002). Treatment with IL-2 alone resulted in a significantly higher number of circulating monocytes (P ¼ 0.037) and intratumoral macrophages (P ¼ 0.005) compared with baseline. In contrast, IL-2/HDC resulted in an unchanged number of circulating monocytes and intratumoral macrophages, and in addition, a significantly increased number of intratumoral CD56 þ NK cells (P ¼ 0.008) and CD8 þ T cells (P ¼ 0.019) compared with baseline. The study provides evidence that circulating monocytes and neutrophils are powerful negative prognostic factors for IL-2-based immunotherapy and establishes a biological rationale for the potential use of histamine in conjunction with IL-2 in mRCC.

Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma

“…Furthermore, we have previously reported an association between pretreatment elevated neutrophil counts in blood and poor prognosis in metastatic renal cell carcinoma and metastatic melanoma. [29][30][31] In the present study, we unfortunately had no full blood count from the patient population. Plasmacytoid dendritic cells (CD123þ) are known to be an important resource of interferons (IFNs) in their activated state.…”

High preoperative neutrophil-lymphocyte ratio predicts poor survival in patients with gastric cancer

“…Recent developments in cancer immunotherapy, and the relationship shown between lymphocyte-neutrophil numbers and prognosis in the present study could be related, and could be exploited to elucidate the response and effectiveness of cancer immunotherapy [20][21][22].…”

Interleukin‐8 modulates growth and invasiveness of estrogen receptor‐negative breast cancer cells

“…16,[18][19][20] Since IL-8 is a critical regulator of neutrophil activation and migration, 21 we postulate that the biological effects of IL-8 in vivo may be associated with its ability to regulate neutrophil infiltration. To test this hypothesis, we used immunocytochemistry to detect neutrophil on frozen tumor tissues.…”