The Molecular Oncology research group, led by Prof. Andrea Alimonti at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+), in close collaboration with the team of Prof. de Bono (Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK), has finally provided the first clinical evidence that myeloid inflammation can fuel disease progression and resistance to hormonal therapies in prostate cancer patients. This study also demonstrated that blockade of intratumor recruitment of immunosuppressive myeloid cells granted durable clinical benefit in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients.
Inflammation is a hallmark of cancer, commonly accompanied by the accumulation of immune cells of myeloid origin capable of inhibiting antitumor immune response and promote tumor growth. Thanks to a specific receptor expressed on their surface, known as CXCR2, these immunosuppressive myeloid cells are attracted into the tumors, where they release nourishing factors. The team led by Prof. Alimonti first demonstrated that immunosuppressive myeloid cells promote prostate cancer aggressiveness and resistance to both chemotherapy and androgen-deprivation therapy, which is the mainstay of treatment for prostate cancer, in experimental mouse models (Di Mitri et al, 2014; Calcinotto et al, Nature, 2018). Despite the evidence that immunosuppressive myeloid cells numbers are increased both in the blood and tumor tissues in patients affected by prostate cancer, whether myeloid inflammation drives prostate cancer progression in humans has remained unclear.
Dr. Christina Guo from RMS/ICR and colleagues from IOR/IOSI conducted a clinical study that finally demonstrated that inhibition of intratumor recruitment of immunosuppressive myeloid cells significantly reduces tumor-elicited inflammation and reverse resistance to androgen-deprivation therapy in patients affected by metatastic prostate cancer. More specifically, they showed that combining CXCR2 inhibitors with drugs blocking androgen receptors, such as enzalutamide, imparted durable clinical benefit with biochemical and radiological responses in a subset of metastatic castration-resistant prostate cancer patients, without dose-limiting toxicity.
This translational study is the first to demonstrate the causal relationship between the accumulation of immunosuppressive myeloid cells and the onset of therapy resistance in prostate cancer patients. More importantly, it showed that the CXCR2 antagonists represent a concrete therapeutic tool to improve clinical outcome of metastatic prostate cancer patients.
"Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance" is the title of the study conducted at the ICR/RMH with the contribution of Dr. Ursula Vogl, Dr. Ilaria Colombo and Dr. Anastasios Stathis from the Oncology Institute of Southern Switzerland (IOSI), Bellinzona.
This study received financial support from the Swiss-Card-Onco-Grant of Alfred and Annemarie von Sick.