Switching the tumor immune microenvironment from “cold” to “hot” in UPS
Undifferentiated Pleiomorphic Sarcoma (UPS) is one of the most aggressive subtypes of soft tissue sarcoma. Besides earlier detection by novel imaging techniques, little has been found to improve the overall survival of these patients in recent years. Novel therapeutic modalities such as immunotherapies have been largely ineffective in many UPS patients. Accordingly, we have found that UPS tumors are most often characterized by a paucity of immune cells, which are excluded from contacting tumor cells. One possible explanation is the heavy presence within UPS of populations of sarcoma associated-fibroblasts (SAFs), which can exclude immune cells from the tumor parenchyma and trap them in the periphery. Studies previously performed on several other types of tumors showed that, based on the immune composition, tumors could be described as inflamed or “hot” if the tumors are highly infiltrated by cytotoxic T cells, or “cold”, if are devoid of immune cells. Although “hot” tumors may be treated by immune interventions (e.g. check-point inhibitors), cold tumors are usually unresponsive. Therefore, the identification of new combinatorial treatments able to switch “cold” tumors into “hot” ones represent a new possibility in cancer immunotherapy.
With respect to this challenge, we will investigate functional characteristics of the various elements comprising the sarcoma microenvironment, including SAFs within the tumor bulk. A number of studies have suggested the possibility to target fibroblasts within epithelial tumors. Such an approach has never been investigated in the context of sarcoma, where the specific populations of SAFs have yet to be identified and characterized. However, we have recently observed that UPS cells, based on their genetic background, attract SAFs within the tumor mass. We will now functionally characterize these SAFs at the single-cell level in order to identify their mechanisms of action. Such characterizations will illuminate new possible interventions based either on the elimination of critical SAFs or of the elements that they use to sustain tumor cells.
In a second approach, we will target critical immune-modulatory elements expressed within tumor cells themselves, thereby promoting tumor immunogenicity. We have observed that several UPS-associated circRNAs regulate immunogenic properties of tumor cells; specifically, their expression inhibits the capacity of the tumor cells to secrete pro-inflammatory cytokines. Based on these data we will target the identified circRNAs in order to re-establish the capacity of tumor cells to release pro-inflammatory cytokines, and thereby to recruit T-cell activity to the TME. Such treatments may ultimately complement conventional interventions and serve as neoadjuvants to increase response to immune approaches in more UPS patients.