Background Intratumoral B-cells are associated with improved survival with ICB in sarcomas.1 We investigated the dynamics of intratumoral and peripheral BCR repertoires and their association with survival in dedifferentiated liposarcoma (DDLPS, n=17) and undifferentiated pleomorphic sarcoma (UPS, n=10) patients treated in a neoadjuvant ICB trial of nivolumab +/- ipilimumab.2-4
Methods Tumor and peripheral blood mononuclear cells (PBMCs) were collected at baseline and surgery. Intratumoral and peripheral BCR heavy (IgH) and light (IgL) chain repertoires were evaluated using bulk RNA sequencing and the TRUST4 algorithm.5 IgH and IgL repertoire diversity and clonality were assessed by inverse Simpson and Gini index, respectively. Comparisons of continuous variables were done using Wilcoxon Rank-Sum test. High and low categories were defined by median values. Comparisons of progression-free survival (PFS) and overall survival (OS) curves were performed by log-rank method. Correlations were assessed using Spearman’s correlation.
Results Tumor transcriptomic data was available for 23 and 20 patients at baseline and surgery, respectively. PBMC transcriptomic data was available for 19 and 23 patients at baseline and surgery, respectively. BCR repertoire diversity increased with ICB, which was significant only in PBMCs (tumor: IgH p=0.077, IgL p=0.11; PBMC: IgH p=0.0065, IgL p=0.029; figures 1 and 2). Neither intratumoral nor peripheral BCR repertoire clonality was impacted by ICB treatment (figures 3 and 4). At baseline, patients with higher IgH BCR diversity had longer PFS (intratumoral: not reached [NR] vs 19 months, p=0.15; peripheral: NR vs 37 months, p=0.25). However, at surgery, patients with higher intratumoral IgH BCR diversity had shorter PFS (17 vs NR months, p=0.024), while peripheral BCR diversity was not associated with PFS (p=0.98). At baseline, patients with higher intratumoral IgH BCR clonality had longer PFS (p=0.19) and significantly longer OS (p=0.022) while neither intratumoral nor peripheral BCR clonality at surgery was associated with survival.
Conclusions ICB is associated with increases in intratumoral and peripheral BCR diversity but not with changes in clonality. Overall, neither the intratumoral IgL nor peripheral IgH and IgL BCR repertoires were associated with survival. Greater diversity of the intratumoral IgH repertoire was a favorable prognostic factor at baseline but a negative one after ICB. These findings warrant future investigations.
Acknowledgements This study was supported by Bristol Myers Squibb. EFN received support from Fondation pour la Recherche Medicale and Fondation Nuovo-Soldati. CLR received support from American College of Surgeons and Society of Surgical Oncology. EZK received support from NCI Early Surgeon Scientist Program.
Trial Registration NCT03307616
Petitprez F, de Reynies A, Keung EZ, Chen TW, Sun CM, Calderaro J, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577(7791):556-60.
Keung EZ-Y, Nassif EF, Lin HY, Lazar AJ, Torres KE, Wang W-L, et al. Randomized phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS): Survival results after 2 years of follow-up and intratumoral B-cell receptor (BCR) correlates. Journal of Clinical Oncology. 2022;40(17_suppl):LBA11501-LBA.
Roland CL, Keung EZ-Y, Lazar AJ, Torres KE, Wang W-L, Guadagnolo A, et al. Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). Journal of Clinical Oncology. 2020;38(15_suppl):11505.
Keung E, Nassif E, Lin H, Lazar A, Wang W-L, Parra E, et al. 379 Immune infiltrates are associated with clinical outcomes in patients with resectable soft tissue sarcoma (STS) treated with neoadjuvant immune checkpoint blockade (ICB). Journal for ImmunoTherapy of Cancer. 2021;9(Suppl 2):A410–A2.
Hu X, Zhang J, Wang J, Fu J, Li T, Zheng X, et al. Landscape of B cell immunity and related immune evasion in human cancers. Nat Genet. 2019;51(3):560–7.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.