Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer

Abstract

The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…Conversely, paclitaxel-induced influx of TAMs was detrimental to chemotherapy response in mouse mammary carcinoma and breast cancer patients. 18,19 Chemotherapy has influence on bone marrow (BM) hematopoiesis, affecting myeloid cell mobilization differentially. A single injection of low-dose CTX was shown to spare DC precursors in the BM, promoting their expansion and differentiation in the peripheral lymphoid organs.…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…There has been extensive research in recent years focusing on the roles of various cells of innate and adaptive immunity that facilitate solid tumour growth by regulating angiogenesis, invasion, and metastasis [4][5][6][7][8], and more recently in regulating the response of tumours to cytotoxic therapy [9][10][11]. Notably lacking from these studies have been in-depth analyses focusing on the role of cancer-associated fibroblasts (CAFs) as inflammatory mediators.…”

Clinical and Biological Implications of the Tumor Microenvironment

“…Moreover, detailed studies on the activated macrophage content of spontaneously-occurring mammary carcinomas in mice showed no correlation with either spontaneous metastatic capability of the tumor nor with the capacity of its cells to colonize downstream organs after intravascular injection [57]. However, it should be mentioned that recently published data [58] have indicated that tumor associated macrophages (TAM) can diminish the efficacy of chemotherapeutic agents and that drugs blocking the cathepsin activity TAM improved the anti-tumor activity of the cytotoxic agents.…”

“…Cancer-stroma-targeting immunoconjugate therapy was thus validated as a new modality of oncological therapy, especially for refractory, stromal-rich cancers. Another method of improving cytotoxic anti-tumor therapy by manipulation of the microenvironment involved blocking cathepsin activity in stromal TAM [58] as mentioned above.…”