Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy: Rationale for combination neoadjuvant immune checkpoint inhibition and radiotherapy

Background: Undifferentiated pleomorphic sarcoma of the extremity and trunk (ET-UPS) presents a unique therapeutic challenge. Although immunotherapy has recently been employed in advanced soft tissue sarcoma, there is limited data characterizing the immune infiltrate in ET-UPS. Radiotherapy (RT) has been shown in other tumor types to promote tumor antigen release and enhance tumor-specific targeting by the adaptive immune system. The aim of this study was to 1) characterize the baseline immune infiltrate and 2) evaluate the effect of preoperative RT on the histologic appearance of and the immune infiltrate in ET-UPS. Methods: We identified 17 matched ET-UPS samples before and after RT. Immunohistochemistry was performed with CD8, CD4, PD-L1, PD1, CD3, CD163 and FoxP3 positive cells identified in all samples. Changes in the immune infiltrate following RT were examined. Results: There was a trend towards increased density of tumor infiltrating immune cells in ET-UPS following RT, with increases in median number of CD3 (158 vs 219 cells/mm(2), p = 0.06), CD4 (3 vs 13 cells/mm(2), p = 0.01), CD8 (55vs 111 cells/mm(2), p = 0.17), and FOXP3 (14 vs 25 cells/mm(2), p = 0.23) positive cells. Interestingly, although PD-L1 was not expressed in any ET-UPS tumor at baseline, positive PD-L1 expression was observed in 21% (3/14) of tumors after RT (p = 0.07). Conclusion: An immune infiltrate is present in ET-UPS at the time of diagnosis, with a trend towards increased density of immune infiltrate and PD-L1 expression after RT. These data support prospectively evaluating immune checkpoint inhibitors with standard of care RT in the treatment of ET-UPS.