Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells
Peter H Goff, Laura Riolobos, Bonnie J LaFleur, Matthew B Spraker, Y David Seo, Kimberly S Smythe, Jean S Campbell, Robert H Pierce, Yuzheng Zhang, Qianchuan He, Edward Y Kim, Stephanie K Schaub, Gabrielle M Kane, Jose G Mantilla, Eleanor Y Chen, Robert Ricciotti, Matthew J Thompson, Lee D Cranmer, Michael J Wagner, Elizabeth T Loggers, Robin L Jones, Erin Murphy, Wendy M Blumenschein, Terrill K McClanahan, Jon Earls, Kevin C Flanagan, Natalie A LaFranzo, Teresa S Kim, Seth M Pollack, Peter H Goff, Laura Riolobos, Bonnie J LaFleur, Matthew B Spraker, Y David Seo, Kimberly S Smythe, Jean S Campbell, Robert H Pierce, Yuzheng Zhang, Qianchuan He, Edward Y Kim, Stephanie K Schaub, Gabrielle M Kane, Jose G Mantilla, Eleanor Y Chen, Robert Ricciotti, Matthew J Thompson, Lee D Cranmer, Michael J Wagner, Elizabeth T Loggers, Robin L Jones, Erin Murphy, Wendy M Blumenschein, Terrill K McClanahan, Jon Earls, Kevin C Flanagan, Natalie A LaFranzo, Teresa S Kim, Seth M Pollack
Abstract
Purpose: To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design.
Experimental design: Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis.
Results: All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy. The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and natural killer (NK) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant radiotherapy with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed postneoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathologic response (≥90% necrosis postneoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T-cell checkpoint TIM3 and downregulation of OX40 were observed posttreatment.
Conclusions: Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for STSs.
Trial registration: ClinicalTrials.gov NCT02923778 NCT03069378 NCT01803152 NCT02180698.
Conflict of interest statement
Conflicts of Interest: The authors have disclosed they have significant relationships with, or financial interest in, the following commercial companies pertaining to this article: PHG received research funding from Gilead Sciences, Inc. outside the submitted work. BL is a paid consultant from Cofactor Genomics, Inc., the company that developed and produces the ImmunoPrism® reagent kit and informatics tools used in this article. JE, KF, and NL are employed by Cofactor Genomics, Inc., which funded and performed the RNA sequencing and ImmunoPrism analysis herein but did not otherwise play a role in the conceptualization, analysis, or presentation of the work herein. LDC received research funding paid to the institution from Eli Lilly, AADi, BluePrint Medicine, Iterion, Gradalis, Philogen, Advenchen Laboratories, and CBA Pharma; LDC has received honoraria or has served on advisory boards for Daichi Sankyo, BluePrint Medicines and Regeneron. JC and RHP are employed by Sensei Biotherapeutics, Inc., which did not play any role in the conceptualization, analysis, or presentation of the work herein. EM, WMB, and TM are employed by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA which funded and performed NanoString nCounter gene expression analysis herein but did not otherwise play a role in the conceptualization, analysis, or presentation of the work herein. SMP reported research funding from Merck during the conduct of the study; research funding from EMD Serono, Incyte, Presage, Janssen, OncoSec, and Juno and consulting, honoraria, and advisory activity with Deciphera, Aadi, Epizyme, Springworks, GlaxoSmithKline, Obsidian, T-knife, Daiichi Sankyo, and Blueprint Medicine, outside the submitted work. MJW reports consulting, honoraria, and advisory activity from Epizyme, Adaptimmune, and Deciphera. The remaining authors declare no potential conflicts of interest.
©2022 American Association for Cancer Research.
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Source: PubMed