Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells

Abstract

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy.

Immuno-PET Molecular Imaging of RANKL in Cancer

“…More recently, the potential for repurposing denosumab as a modulator of the immune response in improving the efficacy of ICI in cancer treatment is actively being explored [ 19 , 20 ]. A phase II study in breast cancer patients supports this approach by showing an increase in lymphocytes and CD8+ T-cells in tumors exposed to single-agent denosumab (D-BEYOND; ClinicalTrials.gov Identifier: NCT01864798) [ 21 ]. Of note are two ongoing randomized trials, one being the CHARLI trial (ClinicalTrials.gov Identifier: NCT03161756) that is a phase Ib/II study including patients with unresectable stage III/IV melanoma treated with nivolumab in combination with four doses of denosumab, with or without ipilimumab (primary end-point: progression-free survival).…”

Significance of CD8+ T cell infiltration-related biomarkers and the corresponding prediction model for the prognosis of kidney renal clear cell carcinoma

“…Previous studies have raised that CD8+ T cell infiltration can play an important role in anti-tumor immunotherapy [ 18 – 22 ]. Indeed, several immunotherapy targets had been identified in CD8+ T cells [ 23 ], suggesting that CD8T should be considered for other anti-cancer therapies.…”

Twelfth Annual ENBDC Workshop: Methods in Mammary Gland Biology and Breast Cancer

“…This immunemodulatory effect of RANK signaling (increased TILS and CD8 + T cells) was confirmed in pre-menopausal early breast cancer patients treated with denosumab in the D-BEYOND trial and is being further investigated in an ongoing clinical trial (D-BIOMARK) treating pre-and post-menopausal women with early breast cancer with neoadjuvant denosumab. Her findings indicate that tumor cells use RANK pathway to evade immune surveillance and support the use of RANK pathway inhibitors to increase response to immunotherapy in luminal breast cancer [12]. She presented new results showing that RANK expression unexpectedly delayed mammary tumor latency in two oncogene-driven mouse models, (MMTV-PyMT and MMTV-Neu).…”