High Serum Levels of IL-6 Predict Poor Responses in Patients Treated with Pembrolizumab plus Axitinib for Advanced Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney malignancy worldwide with Pembrolizumab and axitinib treatment (Pembro/Axi) amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict treatment response and early resistance. Therefore, we evaluated whether baseline serum interleukin-6 (IL-6) could be a predictive biomarker. Between November 2019 and December 2021, 58 patients with advanced RCC were enrolled, administered first-line Pembro/Axi, and baseline blood samples were analyzed using flow cytometry. The mean baseline serum IL-6 concentration was 8.6 pg/mL in responders and 84.1 pg/mL in patients with progressive disease. The IL-6 cut-off value was set at 6.5 pg/mL using time-dependent receiver operating characteristic curves, with 37.9% of patients having high baseline serum IL-6 levels and 62.1% having low levels. Objective response rates were 58.3% and 36.4% in low and high IL-6 groups, respectively. Overall survival and progression-free survival were longer in patients with low IL-6 levels than in those with high levels. High IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production from CD8+ T cells. Overall, high baseline serum IL-6 levels were associated with worse survival outcomes and reduced T-cell responses in Pembro/Axi-treated advanced RCC patients.

Serum cytokines and creatinine/cystatin C ratio as prognostic biomarkers in advanced cancer patients treated with anti-PD-1/PD-L1 therapy

“…Some recent studies have shown an association between high baseline IL-6 levels and reduced bene ts from immunotherapy in hepatocellular carcinoma, melanoma, renal cell carcinoma, and lung cancer patients. [14,[19][20][21]. These studies support our ndings that high level of IL-6 indicates a poor prognosis for advanced cancer patients treated with ICIs.…”

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma

“… 38 Other recent studies have also revealed an association between high baseline IL-6 levels and reduced benefits from immunotherapy in patients with melanoma, renal cell carcinoma, and lung cancer. 22 , 39 , 40 These findings suggest that high IL-6 levels may attenuate the efficacy of immunotherapy and that IL-6 blockade could augment antitumour immunity. A recent preclinical study revealed that IL-6 blockade could suppress tumour growth by enhancing CD4 + /CD8 + effector T cells while suppressing Th17 and macrophages.…”

“… 18 Furthermore, several recent studies have reported mechanisms of resistance to immunotherapy through IL-6 signalling. [19] , [20] , [21] , [22] Excessive activation of IL-6 signalling may attenuate Th1 responses and impair T-cell recruitment in lymph nodes and the tumour microenvironment (TME), thus dampening antitumour T-cell immunity. [23] , [24] , [25] …”

Serum cytokines and creatinine/cystatin C ratio as prognostic biomarkers in advanced cancer patients treated with anti-PD-1/PD-L1 therapy

“…The potential mechanism involves the IL-6-STAT3 signaling pathway, which attenuates the cytotoxic effects of cluster of differentiation 8 positive (CD8 +) T cells and leads to the down-regulation of the expression of major histocompatibility complex class II on the surface of dendritic cells [16][17][18]. Some recent studies have also shown an association between high baseline IL-6 levels and reduced benefits from immunotherapy in hepatocellular carcinoma, melanoma, renal cell carcinoma, lung cancer and cutaneous squamous cell carcinoma patients [14,[19][20][21][22]. These studies support our findings that high level of IL-6 indicates a poor prognosis for advanced cancer patients treated with ICIs.…”