Defining and targeting the mechanisms of post-operative immune suppression in soft tissue sarcoma
Surgery is the only potentially curative treatment of sarcomas, but recurrence in over half of patients limits survival. Successive recurrences of sarcoma are treated with re-operation and tend to have decreasing disease-free intervals, suggesting that surgery itself may be driving accelerated progression of any cancer cells left in the body, termed “hyper-progression”. However, the mechanisms driving worse patient outcomes after surgery are unknown.
The immune system can recognize and respond to cancer. In fact, the immune system is critical for limiting the growth of cancer and driving responses to standard therapies, including chemotherapy, radiation, and immunotherapy. Emerging evidence suggests that surgery itself suppresses the immune system. The consequence is that after surgery, the immune system can no longer control tumor growth, allowing any cancer cells remaining in the body to grow at a significantly accelerated rate and lead to much worse patient survival. And while surgeons always attempt to remove the entirety of a patient’s cancer, this is often not the case. Thus, while surgery can cure a patient with sarcoma, if 100% of cancer cells are not removed then surgery may actually yield worse patient outcomes.
Our objective is to determine specifically which biomolecules and immune cells are involved such that they can be therapeutically targeted at the time of surgery to alleviate immune suppression and abrogate post-operative disease hyper-progression. We have already developed a mouse model of soft tissue sarcoma that recapitulates the human disease course following incomplete tumor resection. We will use this model to define the mechanisms of post-operative immune suppression and potential therapeutic strategies to block post-operative cancer hyper-progression.
This work will be highly clinically relevant by defining the mechanisms that lead to post-operative immune suppression and residual soft tissue sarcoma hyper-progression. This is significant because if culprit mechanisms can be therapeutically blocked at the time of surgery, then patients undergoing surgery (or re-resection) for sarcomas will experience fewer disease recurrences and significantly longer survival.
Targeting these mechanisms at the time of surgery will be highly innovative, providing a novel treatment strategy for patients with soft tissue sarcomas that dramatically reduces recurrence and improves survival. Moreover, we aim to change the paradigm of surgery, turning it from an immune suppressive event into an immune stimulating one. That is, by targeting mechanisms of immune suppression, the inflammation induced by surgery can then be repurposed to promote the anti-tumor immune response and help it to eliminate any residual cancer cells after surgery. In this way, our work will be profoundly impactful for patients with soft tissue sarcomas.