Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells.

Autor:	Goff PH; Department of Radiation Oncology, University of Washington Medicine, Seattle, Washington., Riolobos L; Department of Medicine, University of Washington Medicine, Seattle, Washington.; Department of Cancer Vaccine Institute, University of Washington Medicine, Seattle, Washington., LaFleur BJ; University of Arizona BIO5 Institute, Tucson, Arizona., Spraker MB; Department of Radiation Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Seo YD; Department of Surgery, University of Washington Medicine, Seattle, Washington., Smythe KS; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington., Campbell JS; Sensei Biotherapeutics, Inc., Boston, Massachusetts., Pierce RH; Sensei Biotherapeutics, Inc., Boston, Massachusetts., Zhang Y; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington., He Q; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington., Kim EY; Department of Radiation Oncology, University of Washington Medicine, Seattle, Washington., Schaub SK; Department of Radiation Oncology, University of Washington Medicine, Seattle, Washington., Kane GM; Department of Radiation Oncology, University of Washington Medicine, Seattle, Washington., Mantilla JG; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington., Chen EY; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington., Ricciotti R; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington., Thompson MJ; Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington.; Seattle Cancer Care Alliance, Seattle, Washington., Cranmer LD; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Seattle Cancer Care Alliance, Seattle, Washington.; Department of Medical Oncology, University of Washington Medicine, Seattle, Washington., Wagner MJ; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Seattle Cancer Care Alliance, Seattle, Washington.; Department of Medical Oncology, University of Washington Medicine, Seattle, Washington., Loggers ET; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Seattle Cancer Care Alliance, Seattle, Washington.; Department of Medical Oncology, University of Washington Medicine, Seattle, Washington., Jones RL; Sarcoma, Royal Marsden Hospital NHS Trust/Institute of Cancer Research, London, United Kingdom., Murphy E; Merck & Co., Inc., Kenilworth, New Jersey., Blumenschein WM; Merck & Co., Inc., Kenilworth, New Jersey., McClanahan TK; Merck & Co., Inc., Kenilworth, New Jersey., Earls J; Cofactor Genomics, Inc., San Francisco, California., Flanagan KC; Cofactor Genomics, Inc., San Francisco, California., LaFranzo NA; Cofactor Genomics, Inc., San Francisco, California., Kim TS; Department of Surgery, University of Washington Medicine, Seattle, Washington., Pollack SM; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Apr 14; Vol. 28 (8), pp. 1701-1711.
DOI:	10.1158/1078-0432.CCR-21-4239
Abstrakt:	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. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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