Premetastatic pneumonia. Unrecognized disease-a new target for anticancer therapy
Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B102
At 2:45 p.m.
- Maciej Markiewski - Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX
The concept of the premetastatic niche was introduced more than a century ago, however, until recently the experimental evidence supporting this idea was missing. Growing evidence demonstrates the importance of this niche for spread of cancer. The premetastatic niche is defined as a set of alterations that occur in organs that are targeted by cancer metastasis prior to arrival of tumor cells and facilitate seeding of these organs by tumor cells. Therefore, therapeutic targeting of this niche may prevent metastasis to the vital organs that are responsible for 90% of cancer deaths. We have discovered that the complement anaphylatoxin C5a via the complement C5a receptor 1 (C5aR1) facilitates cancer metastasis by suppressing antitumor immunity in the lung and liver premetastatic niches. The mechanisms behind this metastasis-promoting functions of the C5a/C5aR1 axis involve the recruitment of myeloid-derived suppressor cells (MDSC) to the premetastatic niche and the regulation of cytokine production by these cells. In addition, MDSC-dependent immunosuppression synergizes with immunosuppressive properties of pulmonary alveolar macrophages, which rapidly self-renew in the lungs via C5aR1-mediated mechanisms in tumor-bearing host. Consequently, the premetastatic lungs are heavily infiltrated by alveolar macrophages and MDSC with those latter residing mainly in the lung interalveor septa creating a picture resembling interstitial pneumonia. The pharmacological blockade of C5aR1 synergizes with the depletion of alveolar macrophages in reversing the immunosuppression in the premetastatic niche and reduces or event prevents lung metastasis in a mouse model of breast cancer. Thus, these findings offer a premise for therapeutic targeting of the complement system for anticancer-antimetastatic therapy.
