IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer

Abstract

Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin-1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system, and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis. Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment, and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients.

Combined Photothermal and Photodynamic Therapy for Cancer Treatment Using a Multifunctional Graphene Oxide

“…However, we observed an increase in IL-1β secretion after the incubation of the macrophages with GO–FA and GO–FA/Ce6. This pro-inflammatory cytokine was produced by tumoricidal M1 macrophages, and it is reported that IL-1β is able to inhibit the growth of the primary tumor by impairing the infiltration of innate immune cell subsets with potential anticancer functions, which would help to improve the combined phototherapy for cancer treatment [ 69 ].…”

Muscle and Bone Defects in Metastatic Disease

“…Consistently, formation of the bone metastatic niche was recently demonstrated to be regulated through NAT1/NF-kB/ IL-1ß axis [139]. Tulotta et al demonstrated a dual role of IL1ß, where microenvironment-derived IL-1ß promoted the progression of breast cancer metastases in bone, whereas it inhibited the growth of primary tumor by recruiting innate immune cells with possible anti-tumor roles [140]. Only combined therapy of anakinra with doxorubicin and zoledronic acid exhibited anti-inflammatory effect and markedly inhibited both primary tumor growth and metastatic recurrence in bone.…”

The Ala134Thr variant in TMEM176B exerts a beneficial role in colorectal cancer prognosis by increasing NLRP3 inflammasome activation

“…However, it is important to consider that the IL-1ß effect in cancer is cell-type speci c, being pro-tumorigenic on epithelial cells and anti-tumorigenic on myeloid cells (Dmitrieva-Posocco, 2019) [26]. Some type of cancer, such as breast cancer (Tulotta, 2021) [27], can be bene ted by the treatment with anti-IL-1ß drugs.…”