Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer

Sangeetha M. Reddy, Alexandre Reuben, Souptik Barua, Hong Jiang, Shaojun Zhang, Linghua Wang, Vancheswaran Gopalakrishnan, Courtney W. Hudgens, Michael T. Tetzlaff, James M. Reuben, Takahiro Tsujikawa, Lisa Coussens, Khalida Wani, Yan He, Lily Villareal, Anita Wood, Arvind Rao, Wendy A. Woodward, Naoto T. Ueno, Savitri Krishnamurthy & 2 others Jennifer A. Wargo, Elizabeth A. Mittendorf

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Our understanding is limited concerning the tumor immune microenvironment of inflammatory breast cancer (IBC), an aggressive form of primary cancer with low rates of pathologic complete response to current neoadjuvant chemotherapy (NAC) regimens. We retrospectively identified pretreatment (N = 86) and matched posttreatment tissue (N = 27) from patients with stage III or de novo stage IV IBC who received NAC followed by a mastectomy. Immune profiling was performed including quantification of lymphoid and myeloid infiltrates by IHC and T-cell repertoire analysis. Thirty-four of 86 cases in this cohort (39.5%) achieved a pathologic complete response. Characterization of the tumor microenvironment revealed that having a lower pretreatment mast cell density was significantly associated with achieving a pathologic complete response to NAC (P = 0.004), with responders also having more stromal tumor-infiltrating lymphocytes (P = 0.035), CD8+ T cells (P = 0.047), and CD20+ B cells (P = 0.054). Spatial analysis showed close proximity of mast cells to CD8+ T cells, CD163+ monocytes/macrophages, and tumor cells when pathologic complete response was not achieved. PD-L1 positivity on tumor cells was found in fewer than 2% of cases and on immune cells in 27% of cases, but with no correlation to response. Our results highlight the strong association of mast cell infiltration with poor response to NAC, suggesting a mechanism of treatment resistance and a potential therapeutic target in IBC. Proximity of mast cells to immune and tumor cells may suggest immunosuppressive or tumor-promoting interactions of these mast cells.

Original languageEnglish (US)
Pages (from-to)1025-1035
Number of pages11
JournalCancer Immunology Research
Volume7
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Inflammatory Breast Neoplasms
Mast Cells
Drug Therapy
Tumor Microenvironment
Neoplasms
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Spatial Analysis
Mastectomy
Immunosuppressive Agents
Monocytes
B-Lymphocytes
Cell Count
Macrophages
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer. / Reddy, Sangeetha M.; Reuben, Alexandre; Barua, Souptik; Jiang, Hong; Zhang, Shaojun; Wang, Linghua; Gopalakrishnan, Vancheswaran; Hudgens, Courtney W.; Tetzlaff, Michael T.; Reuben, James M.; Tsujikawa, Takahiro; Coussens, Lisa; Wani, Khalida; He, Yan; Villareal, Lily; Wood, Anita; Rao, Arvind; Woodward, Wendy A.; Ueno, Naoto T.; Krishnamurthy, Savitri; Wargo, Jennifer A.; Mittendorf, Elizabeth A.

In: Cancer Immunology Research, Vol. 7, No. 6, 01.06.2019, p. 1025-1035.

Research output: Contribution to journalArticle

Reddy, SM, Reuben, A, Barua, S, Jiang, H, Zhang, S, Wang, L, Gopalakrishnan, V, Hudgens, CW, Tetzlaff, MT, Reuben, JM, Tsujikawa, T, Coussens, L, Wani, K, He, Y, Villareal, L, Wood, A, Rao, A, Woodward, WA, Ueno, NT, Krishnamurthy, S, Wargo, JA & Mittendorf, EA 2019, 'Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer', Cancer Immunology Research, vol. 7, no. 6, pp. 1025-1035. https://doi.org/10.1158/2326-6066.CIR-18-0619
Reddy, Sangeetha M. ; Reuben, Alexandre ; Barua, Souptik ; Jiang, Hong ; Zhang, Shaojun ; Wang, Linghua ; Gopalakrishnan, Vancheswaran ; Hudgens, Courtney W. ; Tetzlaff, Michael T. ; Reuben, James M. ; Tsujikawa, Takahiro ; Coussens, Lisa ; Wani, Khalida ; He, Yan ; Villareal, Lily ; Wood, Anita ; Rao, Arvind ; Woodward, Wendy A. ; Ueno, Naoto T. ; Krishnamurthy, Savitri ; Wargo, Jennifer A. ; Mittendorf, Elizabeth A. / Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 6. pp. 1025-1035.
@article{07fcc73c31fb4e6e8bf2986117ee6c4b,
title = "Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer",
abstract = "Our understanding is limited concerning the tumor immune microenvironment of inflammatory breast cancer (IBC), an aggressive form of primary cancer with low rates of pathologic complete response to current neoadjuvant chemotherapy (NAC) regimens. We retrospectively identified pretreatment (N = 86) and matched posttreatment tissue (N = 27) from patients with stage III or de novo stage IV IBC who received NAC followed by a mastectomy. Immune profiling was performed including quantification of lymphoid and myeloid infiltrates by IHC and T-cell repertoire analysis. Thirty-four of 86 cases in this cohort (39.5{\%}) achieved a pathologic complete response. Characterization of the tumor microenvironment revealed that having a lower pretreatment mast cell density was significantly associated with achieving a pathologic complete response to NAC (P = 0.004), with responders also having more stromal tumor-infiltrating lymphocytes (P = 0.035), CD8+ T cells (P = 0.047), and CD20+ B cells (P = 0.054). Spatial analysis showed close proximity of mast cells to CD8+ T cells, CD163+ monocytes/macrophages, and tumor cells when pathologic complete response was not achieved. PD-L1 positivity on tumor cells was found in fewer than 2{\%} of cases and on immune cells in 27{\%} of cases, but with no correlation to response. Our results highlight the strong association of mast cell infiltration with poor response to NAC, suggesting a mechanism of treatment resistance and a potential therapeutic target in IBC. Proximity of mast cells to immune and tumor cells may suggest immunosuppressive or tumor-promoting interactions of these mast cells.",
author = "Reddy, {Sangeetha M.} and Alexandre Reuben and Souptik Barua and Hong Jiang and Shaojun Zhang and Linghua Wang and Vancheswaran Gopalakrishnan and Hudgens, {Courtney W.} and Tetzlaff, {Michael T.} and Reuben, {James M.} and Takahiro Tsujikawa and Lisa Coussens and Khalida Wani and Yan He and Lily Villareal and Anita Wood and Arvind Rao and Woodward, {Wendy A.} and Ueno, {Naoto T.} and Savitri Krishnamurthy and Wargo, {Jennifer A.} and Mittendorf, {Elizabeth A.}",
year = "2019",
month = "6",
day = "1",
doi = "10.1158/2326-6066.CIR-18-0619",
language = "English (US)",
volume = "7",
pages = "1025--1035",
journal = "Cancer immunology research",
issn = "2326-6066",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer

AU - Reddy, Sangeetha M.

AU - Reuben, Alexandre

AU - Barua, Souptik

AU - Jiang, Hong

AU - Zhang, Shaojun

AU - Wang, Linghua

AU - Gopalakrishnan, Vancheswaran

AU - Hudgens, Courtney W.

AU - Tetzlaff, Michael T.

AU - Reuben, James M.

AU - Tsujikawa, Takahiro

AU - Coussens, Lisa

AU - Wani, Khalida

AU - He, Yan

AU - Villareal, Lily

AU - Wood, Anita

AU - Rao, Arvind

AU - Woodward, Wendy A.

AU - Ueno, Naoto T.

AU - Krishnamurthy, Savitri

AU - Wargo, Jennifer A.

AU - Mittendorf, Elizabeth A.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Our understanding is limited concerning the tumor immune microenvironment of inflammatory breast cancer (IBC), an aggressive form of primary cancer with low rates of pathologic complete response to current neoadjuvant chemotherapy (NAC) regimens. We retrospectively identified pretreatment (N = 86) and matched posttreatment tissue (N = 27) from patients with stage III or de novo stage IV IBC who received NAC followed by a mastectomy. Immune profiling was performed including quantification of lymphoid and myeloid infiltrates by IHC and T-cell repertoire analysis. Thirty-four of 86 cases in this cohort (39.5%) achieved a pathologic complete response. Characterization of the tumor microenvironment revealed that having a lower pretreatment mast cell density was significantly associated with achieving a pathologic complete response to NAC (P = 0.004), with responders also having more stromal tumor-infiltrating lymphocytes (P = 0.035), CD8+ T cells (P = 0.047), and CD20+ B cells (P = 0.054). Spatial analysis showed close proximity of mast cells to CD8+ T cells, CD163+ monocytes/macrophages, and tumor cells when pathologic complete response was not achieved. PD-L1 positivity on tumor cells was found in fewer than 2% of cases and on immune cells in 27% of cases, but with no correlation to response. Our results highlight the strong association of mast cell infiltration with poor response to NAC, suggesting a mechanism of treatment resistance and a potential therapeutic target in IBC. Proximity of mast cells to immune and tumor cells may suggest immunosuppressive or tumor-promoting interactions of these mast cells.

AB - Our understanding is limited concerning the tumor immune microenvironment of inflammatory breast cancer (IBC), an aggressive form of primary cancer with low rates of pathologic complete response to current neoadjuvant chemotherapy (NAC) regimens. We retrospectively identified pretreatment (N = 86) and matched posttreatment tissue (N = 27) from patients with stage III or de novo stage IV IBC who received NAC followed by a mastectomy. Immune profiling was performed including quantification of lymphoid and myeloid infiltrates by IHC and T-cell repertoire analysis. Thirty-four of 86 cases in this cohort (39.5%) achieved a pathologic complete response. Characterization of the tumor microenvironment revealed that having a lower pretreatment mast cell density was significantly associated with achieving a pathologic complete response to NAC (P = 0.004), with responders also having more stromal tumor-infiltrating lymphocytes (P = 0.035), CD8+ T cells (P = 0.047), and CD20+ B cells (P = 0.054). Spatial analysis showed close proximity of mast cells to CD8+ T cells, CD163+ monocytes/macrophages, and tumor cells when pathologic complete response was not achieved. PD-L1 positivity on tumor cells was found in fewer than 2% of cases and on immune cells in 27% of cases, but with no correlation to response. Our results highlight the strong association of mast cell infiltration with poor response to NAC, suggesting a mechanism of treatment resistance and a potential therapeutic target in IBC. Proximity of mast cells to immune and tumor cells may suggest immunosuppressive or tumor-promoting interactions of these mast cells.

UR - http://www.scopus.com/inward/record.url?scp=85067217335&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067217335&partnerID=8YFLogxK

U2 - 10.1158/2326-6066.CIR-18-0619

DO - 10.1158/2326-6066.CIR-18-0619

M3 - Article

VL - 7

SP - 1025

EP - 1035

JO - Cancer immunology research

JF - Cancer immunology research

SN - 2326-6066

IS - 6

ER -