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 - 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 -