Abstract PR002: Antigen presentation and processing pathway is associated with early relapse after neoadjuvant immune checkpoint blockade (ICB) in dedifferentiated liposarcomas (DDLPS)
Authors: Nassif Elise F. , Wu Chia-Chin , Akdemir Kadir , Witt Russell G. , Traweek Raymond , Cope Brandon , Thirasastr Prapassorn , Tate Taylor , Mathew Grace , Crosby Shadarra , Chu Randy , Mohammad Mohammad , Shaw Kenna , Davis Ingram , Wani Khalida , Lazar Alexander J. , Wang Wei-Lien , Duncan Sheila , Guadagnolo Ashleigh B. , Bishop Andrew J. , Lewis Valerae , Bird Justin E. , Torres Keila E. , Hunt Kelly K. , Feig Barry W. , Scally Christopher P. , Ratan Ravin , Patel Shreyaskumar , Benjamin Robert S. , Satcher Robert , McBride Kevin , Fridman Wolf H. , Wistuba Ignacio , Futreal Andrew , Wargo Jennifer A. , Somaiah Neeta , Roland Christina L. , Keung Emily Z. 
Published: September 2022

Abstract
Background: We evaluated the activity of neoadjuvant ICB in localized resectable DDLPS (n=17) and undifferentiated pleomorphic sarcomas (UPS; n=10). DDLPS and UPS patients were randomized to neoadjuvant nivolumab or ipilimumab+nivolumab, with UPS patients receiving concurrent radiotherapy. We assessed genomic markers of early relapse (progression before surgery or relapse within 52 weeks following surgery) using longitudinally acquired tumor samples. Methods: RNA sequencing (RNAseq) and whole genome sequencing (WGS) were performed on longitudinally acquired samples (baseline biopsies and surgical specimens). Differential gene expression between any two groups of patients (i.e., non-early relapse [non-relapsers] vs early relapse [relapsers]) were selected (fold change&gt;1.5 and p value&lt;0.05). Gene set enrichment analyses (GSEA) of KEGG pathways were performed and a network-based approach used to identify genes/pathways associated with MHC-I. Results: At a median follow-up of 23 months, 12 patients (9 DDLPS, 3 UPS) relapsed, including 7 early relapses (relapsers: 5 DDLPS, 2 UPS). The median relapse-free survival was 22 months in DDLPS patients (6 months in relapsers; not reached [NR] in non-relapsers) and NR in UPS patients. At baseline, the most differentially upregulated pathways in non-relapsers compared to relapsers were “graft versus host disease” (GSEA Normalized Enrichment Score[NES]=2.25; False Discovery Rate[FDR] q= 0.009), “natural killer cell mediated cytotoxicity” (NES=2.17; FDR q=0.009), “antigen processing and presentation” (NES=2.16; FDR q=0.009), “allograft rejection” (NES=1.99; FDR q=0.019) and “B-cell receptor signaling pathway” (NES=1.87; FDR q=0.018). In DDLPS patients, the antigen presentation and processing pathway was the most upregulated pathway in non-relapsers compared to relapsers (NES=2.01; FDR q=0.025) while it was not significantly upregulated in UPS (NES=1.15; FDR q=0.62). When looking at pathways longitudinally, the antigen presentation and processing pathway was significantly upregulated at surgery compared to baseline in DDLPS. As antigen presentation and processing was significantly upregulated in DDLPS patients and associated with relapse, we looked for expressed neoantigens that may be processed and presented. Using WGS, we detected 5712 rearrangements at baseline in DDLPS, of which 230 were found in more than one tumor specimen. We also sought to identify genes associated with MHC-I. We selected genes upregulated during ICB comparing baseline to surgical specimens in DDLPS relapsers and looked at the top 10% of genes associated with MHC-I in order to identify potential therapeutic targets for combination. We identified 41 genes upregulated during ICB and associated with MHC-I in relapsers, for which up to 275 inhibitory compounds were found in drug databases. Conclusion: Antigen presentation and processing is a major driver of response to immunotherapy. Future efforts should focus on identifying which antigens are presented to find synergizing compounds in order to increase the clinical benefit of ICB.
Citation Format: Elise F. Nassif, Chia-Chin Wu, Kadir Akdemir, Russell G. Witt, Raymond Traweek, Brandon Cope, Prapassorn Thirasastr, Taylor Tate, Grace Mathew, Shadarra Crosby, Randy Chu, Mohammad Mohammad, Kenna Shaw, Ingram Davis, Khalida Wani, Alexander J. Lazar, Wei-Lien Wang, Sheila Duncan, Ashleigh B. Guadagnolo, Andrew J. Bishop, Valerae Lewis, Justin E. Bird, Keila E. Torres, Kelly K. Hunt, Barry W. Feig, Christopher P. Scally, Ravin Ratan, Shreyaskumar Patel, Robert S. Benjamin, Robert Satcher, Kevin McBride, Wolf H. Fridman, Ignacio Wistuba, Andrew Futreal, Jennifer A. Wargo, Neeta Somaiah, Christina L. Roland, Emily Z. Keung. Antigen presentation and processing pathway is associated with early relapse after neoadjuvant immune checkpoint blockade (ICB) in dedifferentiated liposarcomas (DDLPS) [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR002.