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

doi:10.1158/1078-0432.CCR-21-4239

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. LoggersRobin L. Jones, Erin Murphy, Wendy M. Blumenschein, Terrill K. McClanahan, Jon Earls, Kevin C. Flanagan, Natalie A. LaFranzo, Teresa S. Kim, Seth M. Pollack^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1701-1711
Number of pages	11
Journal	Clinical Cancer Research
Volume	28
Issue number	8
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-4239
State	Published - Apr 15 2022

Funding

This work was supported by CA180380 and the Sarcoma Foundation of America (to S.M. Pollack). NanoString assays were performed by Merck & Co., Inc. RNA-seq with ImmunoPrism was performed by Cofactor Genomics. S.M. Pollack was also supported by R01CA244872, CA180380, a grant from the V Foundation, and the Seattle Translational Tumor Research (STTR). The Experimental Histopathology Shared Resource at the Fred Hutchinson Cancer Research Center was supported by the NIH P30 CA015704 Cancer Center Support Grant. We thank members of the Fred Hutchinson Cancer Research Center Experimental Histopathology Core Facility for assistance with multiplex IHC and image analysis. We thank Dr. Venu Pillarisetty for helpful discussions, and Ms. Silvia Christian for administrative support. This work was supported by CA180380 and the Sarcoma Foundation of America (to S.M. Pollack). NanoString assays were performed by Merck & Co., Inc. RNA-seq with ImmunoPrism was performed by Cofactor Genomics. S.M. Pollack was also supported by R01CA244872, CA180380, a grant from the V Foundation, and the Seattle Translational Tumor Research (STTR). The Experimental Histopathology Shared Resource at the Fred Hutchinson Cancer Research Center was supported by the NIH P30 CA015704 Cancer Center Support Grant.

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1078-0432.CCR-21-4239

Cite this

Goff, P. H., Riolobos, L., LaFleur, B. J., Spraker, M. B., Seo, Y. D., Smythe, K. S., Campbell, J. S., Pierce, R. H., Zhang, Y., He, Q., Kim, E. Y., Schaub, S. K., Kane, G. M., Mantilla, J. G., Chen, E. Y., Ricciotti, R., Thompson, M. J., Cranmer, L. D., Wagner, M. J., ... Pollack, S. M. (2022). Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells. Clinical Cancer Research, 28(8), 1701-1711. https://doi.org/10.1158/1078-0432.CCR-21-4239

@article{db61e7da562445c3a223dae53df7ee4d,

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

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.",

author = "Goff, {Peter H.} and Laura Riolobos and LaFleur, {Bonnie J.} and Spraker, {Matthew B.} and Seo, {Y. David} and Smythe, {Kimberly S.} and Campbell, {Jean S.} and Pierce, {Robert H.} and Yuzheng Zhang and Qianchuan He and Kim, {Edward Y.} and Schaub, {Stephanie K.} and Kane, {Gabrielle M.} and Mantilla, {Jose G.} and Chen, {Eleanor Y.} and Robert Ricciotti and Thompson, {Matthew J.} and Cranmer, {Lee D.} and Wagner, {Michael J.} and Loggers, {Elizabeth T.} and Jones, {Robin L.} and Erin Murphy and Blumenschein, {Wendy M.} and McClanahan, {Terrill K.} and Jon Earls and Flanagan, {Kevin C.} and LaFranzo, {Natalie A.} and Kim, {Teresa S.} and Pollack, {Seth M.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

month = apr,

day = "15",

doi = "10.1158/1078-0432.CCR-21-4239",

language = "English (US)",

volume = "28",

pages = "1701--1711",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "8",

}

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 2022, 'Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells', Clinical Cancer Research, vol. 28, no. 8, pp. 1701-1711. https://doi.org/10.1158/1078-0432.CCR-21-4239

TY - JOUR

T1 - Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells

AU - Goff, Peter H.

AU - Riolobos, Laura

AU - LaFleur, Bonnie J.

AU - Spraker, Matthew B.

AU - Seo, Y. David

AU - Smythe, Kimberly S.

AU - Campbell, Jean S.

AU - Pierce, Robert H.

AU - Zhang, Yuzheng

AU - He, Qianchuan

AU - Kim, Edward Y.

AU - Schaub, Stephanie K.

AU - Kane, Gabrielle M.

AU - Mantilla, Jose G.

AU - Chen, Eleanor Y.

AU - Ricciotti, Robert

AU - Thompson, Matthew J.

AU - Cranmer, Lee D.

AU - Wagner, Michael J.

AU - Loggers, Elizabeth T.

AU - Jones, Robin L.

AU - Murphy, Erin

AU - Blumenschein, Wendy M.

AU - McClanahan, Terrill K.

AU - Earls, Jon

AU - Flanagan, Kevin C.

AU - LaFranzo, Natalie A.

AU - Kim, Teresa S.

AU - Pollack, Seth M.

PY - 2022/4/15

Y1 - 2022/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85128301568&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85128301568&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-21-4239

DO - 10.1158/1078-0432.CCR-21-4239

M3 - Article

C2 - 35115306

AN - SCOPUS:85128301568

SN - 1078-0432

VL - 28

SP - 1701

EP - 1711

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 8

ER -

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this