Towards precision immunotherapy for undifferentiated pleomorphic sarcoma (UPS)

A tumor must evade destruction by the host’s immune system in order to grow. Immunotherapy works by enhancing or restoring the anti-tumor effects of the immune system. Checkpoint blockade has demonstrated efficacy in multiple tumor types and has revolutionized their management. Initial trials of checkpoint blockade therapy in unselected sarcomas have generally shown low objective response rates (ORR). However, the anti-PD1 monoclonal antibody pembrolizumab demonstrated an ORR of 44% in patients with undifferentiated pleomorphic sarcoma (UPS), indicating a potential role for immunotherapy in certain sarcomas. An area of on-going research is understanding why most other subtypes of sarcoma, along with the majority of patients with UPS, do not respond to checkpoint blockade. We hypothesize that by analyzing the tumor and the intratumoral immune response in surgical specimens, we can determine the specific immune evasion mechanisms utilized by individual tumors. This information can be used to optimize immunotherapy and thereby broaden the applicability of immunotherapy in sarcoma.

We propose to extend our initial computational characterization of the immune infiltrate of the 50 UPS specimens within the Cancer Genome Atlas sarcoma dataset. Our results will identify a set of candidate UPS-specific immune regulatory pathways and molecules. We will validate the results of this in-silico analysis using a flow cytometry and immunohistochemistry (IHC) based intratumoral immune analysis in independent UPS tumor samples from our institution. We have already completed this analysis on 4 of a planned 20 samples. We will then functionally test the effects of modulating the activity of these UPS-specific immune modulatory pathways in an established murine model of UPS. This study would represent the first experimental validation of expression-based immune infiltrate estimation methods in sarcoma. It would provide a framework to identify tumor-specific mechanisms of immune escape and preclinical rationale for basing therapy on the characteristics of an individual’s tumor immune infiltrate. Our long-term goal is to provide each sarcoma patient with an evaluation of the mechanisms of immune evasion utilized by their tumor. This information would be used to increase the efficacy of their treatment by directing personalized immunotherapy.