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Breast Cancer Research
Published in: Breast Cancer Research 1/2021

01-12-2021 | Breast Cancer | Research article

Plasma cell infiltration and treatment effect in breast cancer patients treated with neoadjuvant chemotherapy

Authors: Asumi Sakaguchi, Yoshiya Horimoto, Hiroko Onagi, Daiki Ikarashi, Takayuki Nakayama, Tetsuya Nakatsura, Hideo Shimizu, Kuniaki Kojima, Takashi Yao, Toshiharu Matsumoto, Kanako Ogura, Shigehisa Kitano

Published in: Breast Cancer Research | Issue 1/2021

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Abstract

Background

Tumour-infiltrating lymphocyte (TIL)-high breast tumours have a high rate of pathological complete response (pCR) with neoadjuvant chemotherapy. In our routine pathological diagnoses of biopsy specimens from pCR cases, we have observed a high infiltration of plasma cells (PCs). A positive correlation of PCs with favourable patient outcome has recently been reported, but little is known about how PCs contribute to local tumour immunity.

Methods

We retrospectively examined biopsy specimens from 146 patients with invasive breast cancer who received neoadjuvant chemotherapy. CD138+ PC infiltration was assessed by immunohistochemistry. Multiplexed fluorescent immunohistochemistry (mfIHC) with T and B cell markers was also conducted to elucidate the profile of immune cells.

Results

Greater PC infiltration was observed in the pCR group (p = 0.028) and this trend was confirmed in another patient cohort. With mfIHC, we observed significantly more CD8+, T-bet+CD4+, and CD8+FOXP3+ T cells, total B cells and PCs in pCR cases. Such cases were also characterised by high expression of both PD-1 and PD-L1 on B cells and PCs. In patients with hormone receptor-negative tumours, high PC infiltration was correlated with significantly longer disease-free survival (p = 0.034).

Conclusions

We found that higher PC infiltration in biopsy specimens before neoadjuvant chemotherapy was associated with pCR. With mfIHC, we also revealed that the local cytotoxic immune response was clearly enhanced in pCR cases, as was the infiltration of B cells including PCs. Moreover, higher PC levels were correlated with favourable outcomes in hormone receptor-negative breast cancer patients.
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Literature
1.
Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206–23.CrossRef
2.
Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32.CrossRef
3.
Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278–84.CrossRef
4.
Fasching PA, Jackisch C, Rhiem K, Schneeweiss A, Klare P, Hanusch C et al. GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD). J Clin Oncol. 2019;37(15_suppl):506–506.
5.
Barranco C. Sensitivity to preoperative chemotherapy varies between breast cancer subtypes. Nat Clin Pract Oncol. 2005;2(12):600–600.CrossRef
6.
Horimoto Y, Arakawa A, Harada-Shoji N, Sonoue H, Yoshida Y, Himuro T, et al. Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases. Br J Cancer. 2015;112(2):345–51.CrossRef
7.
Denkert C, Loibl S, Müller BM, Eidtmann H, Schmitt WD, Eiermann W, et al. Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial. Ann Oncol. 2013;24(11):2786–93.CrossRef
8.
Horimoto Y, Arakawa A, Tanabe M, Sonoue H, Igari F, Senuma K, et al. Ki67 expression and the effect of neo-adjuvant chemotherapy on luminal HER2-negative breast cancer. BMC Cancer. 2014;14:550.CrossRef
9.
Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105(1):93–103.CrossRef
10.
Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32(27):2959–66.CrossRef
11.
Saltz J, Gupta R, Hou L, Kurc T, Singh P, Nguyen V, et al. Spatial organization and molecular correlation of tumor-infiltrating lymphocytes using deep learning on pathology images. Cell Rep. 2018;23(1):181-193.e187.CrossRef
12.
Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–21.CrossRef
13.
Zou Y, Zou X, Zheng S, Tang H, Zhang L, Liu P, et al. Efficacy and predictive factors of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis. Ther Adv Med Oncol. 2020;12:1758835920940928–1758835920940928.CrossRef
14.
Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33(9):983–91.CrossRef
15.
Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, et al. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer. 2013;109(10):2705–13.CrossRef
16.
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.CrossRef
17.
Bianchini G, Gianni L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol. 2014;15(2):e58-68.CrossRef
18.
Galluzzi L, Zitvogel L, Kroemer G. Immunological mechanisms underneath the efficacy of cancer therapy. Cancer Immunol Res. 2016;4(11):895–902.CrossRef
19.
Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938–45.CrossRef
20.
Yeong J, Lim JCT, Lee B, Li H, Chia N, Ong CCH, et al. High densities of tumor-associated plasma cells predict improved prognosis in triple negative breast cancer. Front Immunol. 2018;9:1209.CrossRef
21.
Tsuda H, Tsugawa K, Akiyama F, Horii R, Kurosumi M, Moriya T, et al. Histological classification of breast tumors in the general rules for clinical and pathological recording of breast cancer. Breast Cancer. 2020;27(3):309–21.CrossRef
22.
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71.CrossRef
23.
Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17(5):1474–81.CrossRef
24.
Iwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ, et al. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry. J Clin Oncol. 2012;30(7):729–34.CrossRef
25.
Honma N, Horii R, Iwase T, Saji S, Younes M, Ito Y, et al. Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy. Breast. 2014;23(6):754–62.CrossRef
26.
Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol. 2020;20(5):294–307.CrossRef
27.
Belz GT, Kallies A. Effector and memory CD8+ T cell differentiation: toward a molecular understanding of fate determination. Curr Opin Immunol. 2010;22(3):279–85.CrossRef
28.
Khader SA, Partida-Sanchez S, Bell G, Jelley-Gibbs DM, Swain S, Pearl JE, et al. Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J Exp Med. 2006;203(7):1805–15.CrossRef
29.
Wilson DC, Matthews S, Yap GS. IL-12 signaling drives CD8+ T cell IFN-γ production and differentiation of KLRG1+ Effector Subpopulations during Toxoplasma gondii Infection. J Immunol. 2008;180(9):5935–45.CrossRef
30.
Morgan EL, Hobbs MV, Thoman MT, Weigle WO. Lymphocyte activation by the Fc region of immunoglobulins. Immunol Invest. 1986;15(7):625–87.CrossRef
31.
Takai T. Roles of Fc receptors in autoimmunity. Nat Rev Immunol. 2002;2(8):580–92.CrossRef
32.
Kara S, Amon L, Lühr JJ, Nimmerjahn F, Dudziak D, Lux A. Impact of plasma membrane domains on IgG Fc receptor function. Front Immunol. 2020;11:1320.CrossRef
33.
Abdi K, Singh NJ, Spooner E, Kessler BM, Radaev S, Lantz L, et al. Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly. J Immunol. 2014;192(12):6028–36.CrossRef
34.
Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251–76.CrossRef
35.
Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–29.CrossRef
36.
Schülke S. Induction of interleukin-10 producing dendritic cells as a tool to suppress allergen-specific T helper 2 responses. Front Immunol. 2018;9:455.CrossRef
37.
Iglesia MD, Vincent BG, Parker JS, Hoadley KA, Carey LA, Perou CM, et al. Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer. Clin Cancer Res. 2014;20(14):3818–29.CrossRef
Metadata
Title
Plasma cell infiltration and treatment effect in breast cancer patients treated with neoadjuvant chemotherapy
Authors
Asumi Sakaguchi
Yoshiya Horimoto
Hiroko Onagi
Daiki Ikarashi
Takayuki Nakayama
Tetsuya Nakatsura
Hideo Shimizu
Kuniaki Kojima
Takashi Yao
Toshiharu Matsumoto
Kanako Ogura
Shigehisa Kitano
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2021
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-021-01477-w

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