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 M.
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.
N1 - Funding Information:
V. Gopalakrishnan has received honoraria from the speakers bureau of the Kansas Society of Clinical Oncology and Excel CME, has ownership interest (including stock, patents, etc.) in UT MD Anderson Cancer Center, and is a consultant/advisory board member for MicrobiomeDX and Expert-Connect. M.T. Tetzlaff is a consultant/advisory board member for Novartis, LLC, Myriad Genetics, and Seattle Genetics. L.M. Coussens reports receiving commercial research grants from Acerta Pharma, LLC, Deciphera Pharmaceuticals, LLC, Roche Glycart AG, and Syndax Pharmaceuticals, Inc., reports receiving other commercial research support from Plexxikon Inc., Pharma-cyclics, Inc., Acerta Pharma, LLC, Deciphera Pharmaceuticals, LLC, Genentech, Inc., Roche Glycart AG, Cell Signaling Technology, and Nano-String Technologies, Inc., is a consultant/advisory board member for Phar-macyclics, Inc. steering committee for PCYC-1137-CA (NCT02436668), Syndax Pharmaceuticals, Inc. External Advisory Board, Cancer Research Institute (CRI), The V Foundation for Cancer Research, Cancer Research United Kingdom (CRUK) Early Detection (EDx) Research Committee, Starr Cancer Consortium, NIH/NCI-Frederick National Laboratory Advisory Committee (FNLAC), Cell Signaling Technology; Carisma Therapeutics Inc. Scientific Advisory Board, Verseau Therapeutics, Inc, Scientific Advisory Board, Zymeworks, Inc. Scientific Advisory Board, (P30) Melvin and Bren Simon Cancer Center, Indiana University, (P30) Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, (P30) Salk Institute Cancer Center, Bloomberg–Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Dana Farber Cancer Center Breast SPORE. A. Rao is a member of Voxel Analytics, reports receiving other commercial research support from Agilent Technologies, and is a consultant/advisory board member for Deoxylitics. N.T. Ueno reports receiving a commercial research grant from Amgen and Celgene. J.A. Wargo has received honoraria from the speakers bureau of Dava Oncology, Illumina, and PHE and is a consultant/advisory board member for Bristol-Myers Squibb, Novartis, Roche, Genentech, AstraZeneca, and Merck. E.A. Mittendorf is a consultant/advisory board member for Merck, Sellas Lifesciences, AstraZeneca, TapImmune, Peregrine Pharmaceuticals, and Genentech. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This research was funded by the Breast Cancer Research Foundation/ Conquer Cancer Foundation Young Investigator Award (to S.M. Reddy), Breast Cancer Research Foundation (to N.T. Ueno), Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, State of Texas Rare and Aggressive Breast Cancer Research Program Grant, and the MD Anderson Cancer Center Support grant (NCI #CA16672). S.M. Reddy received support from NIH T32 Training Grant T32 CA 009666. A. Reuben received support from the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson's Odyssey Fellowship Program. A. Rao received
Funding Information:
This research was funded by the Breast Cancer Research Foundation/ Conquer Cancer Foundation Young Investigator Award (to S.M. Reddy), Breast Cancer Research Foundation (to N.T. Ueno), Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, State of Texas Rare and Aggressive Breast Cancer Research Program Grant, and the MD Anderson Cancer Center Support grant (NCI #CA16672). S.M. Reddy received support from NIH T32 Training Grant T32 CA 009666. A. Reuben received support from the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson's Odyssey Fellowship Program. A. Rao received support from the CCSG Bioinformatics Shared Resource P30 CA016672, an Institutional Research Grant from The University of Texas MD Anderson Cancer Center, CPRIT RP170719, CPRIT RP150578, NCI R01CA214955- 01A1, a Career Development Award from the MD Anderson Brain Tumor SPORE, a gift from Agilent technologies, and a Research Scholar Grant from the American Cancer Society (RSG-16-005-01). E.A. Mittendorf received support from the Pink Ribbons Project
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/6
Y1 - 2019/6
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.
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U2 - 10.1158/2326-6066.CIR-18-0619
DO - 10.1158/2326-6066.CIR-18-0619
M3 - Article
C2 - 31043414
AN - SCOPUS:85067217335
SN - 2326-6066
VL - 7
SP - 1025
EP - 1035
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 6
ER -