Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells.
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Embargo End Date
ICR Authors
Authors
Goff, PH
Riolobos, L
LaFleur, BJ
Spraker, MB
Seo, YD
Smythe, KS
Campbell, JS
Pierce, RH
Zhang, Y
He, Q
Kim, EY
Schaub, SK
Kane, GM
Mantilla, JG
Chen, EY
Ricciotti, R
Thompson, MJ
Cranmer, LD
Wagner, MJ
Loggers, ET
Jones, RL
Murphy, E
Blumenschein, WM
McClanahan, TK
Earls, J
Flanagan, KC
LaFranzo, NA
Kim, TS
Pollack, SM
Riolobos, L
LaFleur, BJ
Spraker, MB
Seo, YD
Smythe, KS
Campbell, JS
Pierce, RH
Zhang, Y
He, Q
Kim, EY
Schaub, SK
Kane, GM
Mantilla, JG
Chen, EY
Ricciotti, R
Thompson, MJ
Cranmer, LD
Wagner, MJ
Loggers, ET
Jones, RL
Murphy, E
Blumenschein, WM
McClanahan, TK
Earls, J
Flanagan, KC
LaFranzo, NA
Kim, TS
Pollack, SM
Document Type
Journal Article
Date
2022-04-14
Date Accepted
2022-02-01
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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2022, 28 (8), pp. 1701 - 1711
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Sarcoma Clinical Trials (R Jones)