Abstract 7124: Imaging mass cytometry (IMC) reveals distinct intratumoral B and T regulatory cell populations in responder versus non-responder soft tissue sarcoma (STS) patients before treatment with immune checkpoint blockade (ICB)
Authors: Laurence P. Diggs, Elise Nassif Haddad, Susmita Kumari, Varshini Arunkumar, Sammy Ferri-Borgogno, Samuel Mok, Duncan Mak, Angelique Lin, Madeline McAllister, Akshay Basi, Manoj Chelvanambi, Javier Gomez, Jared Burks, Davis Ingram, Khalida Wani, Natalie Duarte, Trevor McKee, Alexander Lazar, Jennifer Wargo, Christina Roland, Emily Keung
Journal: Cancer Research (2025)

Abstract Background: STS are poorly understood cancers for which systemic therapy options are limited. Recent evidence suggests that some patients with two types of STS (undifferentiated pleomorphic sarcoma, UPS; dedifferentiated liposarcoma, DDLPS) benefit from ICB. Presence of tertiary lymphoid structures (TLS) and B cells within the sarcoma tumor immune microenvironment (TME) is associated with response to ICB and longer survival. It remains unclear how immune populations within this TME interact with each other and how they evolve upon ICB exposure. We characterized the TLS composition and spatial relationships between immune populations in untreated biopsies of UPS/DDLPS of responders (R) versus non-responders (NR). Methods: We completed a phase 2 trial of patients with resectable primary UPS (n=10) and DDLPS (n=17) who received ICB prior to surgery. Pre-ICB treatment biopsies were collected, and IMC was performed using a 34-plex antibody panel to characterize the TME of R vs NR. TLS composition, densities of immune cell subsets, and their spatial relationships were assessed across baseline biopsy specimens within 3 pre-defined regions-of-interest (ROIs): TLS, non-TLS, and TLS-non-TLS interface regions. Results: We identified distinct TME profiles in R compared to NR prior to ICB treatment. Intratumoral B cell density was higher in R compared to NR patients across pre-treatment biopsies (502 vs 277 cells/mm2, p=0.45) and within interface (1155 vs 710 cells/mm2, p=0.42) and non-TLS (458 vs 257 cells/mm2, p=0.17) regions but lower in TLS regions (506 vs 729 cells/mm2, p=0.52). NR patients tended to have higher densities of Tregs across pre-treatment samples (81 vs 37 cells/mm2, p=0.44) and in TLS (981 vs 824 cells/mm2, p=0.59), interface (119 vs 53 cells/mm2, p=0.14), and non-TLS (66 vs 15 cells/mm2, p&amp;lt;0.01) regions. When examining spatial distributions of TME immune populations, we noted a trend towards greater distances between B cells and T regs in the tumors of R compared to NR patients (78 vs 45 microns, p=0.13) which was also observed in TLS (116 vs 40 microns, p=0.05), non-TLS (76 vs 44 microns, p=0.14), and interface (179 vs 41 microns, p&amp;lt;0.01) regions. Conclusion: Although presence of intratumoral TLS is associated with ICB response and longer survival among patients with UPS/DDLPS, not everyone benefits. Response to ICB appears to be associated with the immune profile both within and beyond TLS regions of pre-treatment tumors. Lower Treg, higher B cell populations, and greater distances between Tregs and B cells within pre-treatment biopsies may help predict response to ICB for UPS and DDLPS. Studies are ongoing to assess the evolution of these spatial relationships after ICB treatment. Citation Format: Laurence P. Diggs, Elise Nassif Haddad, Susmita Kumari, Varshini Arunkumar, Sammy Ferri-Borgogno, Samuel Mok, Duncan Mak, Angelique Lin, Madeline McAllister, Akshay Basi, Manoj Chelvanambi, Javier Gomez, Jared Burks, Davis Ingram, Khalida Wani, Natalie Duarte, Trevor McKee, Alexander Lazar, Jennifer Wargo, Christina Roland, Emily Keung. Imaging mass cytometry (IMC) reveals distinct intratumoral B and T regulatory cell populations in responder versus non-responder soft tissue sarcoma (STS) patients before treatment with immune checkpoint blockade (ICB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7124.