The Immunology of Hormone Receptor Positive Breast Cancer

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Jun 17

PMID 34135901

Citations 58

Authors

Jonathan Goldberg

Ricardo G Pastorello

Tuulia Vallius

Janae Davis

Yvonne Xiaoyong Cui

Judith Agudo

Adrienne G Waks

Tanya Keenan

Sandra S McAllister

Sara M Tolaney

Elizabeth A Mittendorf

Jennifer L Guerriero

Affiliations

Soon will be listed here.

Abstract

Immune checkpoint blockade (ICB) has revolutionized the treatment of cancer patients. The main focus of ICB has been on reinvigorating the adaptive immune response, namely, activating cytotoxic T cells. ICB has demonstrated only modest benefit against advanced breast cancer, as breast tumors typically establish an immune suppressive tumor microenvironment (TME). Triple-negative breast cancer (TNBC) is associated with infiltration of tumor infiltrating lymphocytes (TILs) and patients with TNBC have shown clinical responses to ICB. In contrast, hormone receptor positive (HR+) breast cancer is characterized by low TIL infiltration and minimal response to ICB. Here we review how HR+ breast tumors establish a TME devoid of TILs, have low HLA class I expression, and recruit immune cells, other than T cells, which impact response to therapy. In addition, we review emerging technologies that have been employed to characterize components of the TME to reveal that tumor associated macrophages (TAMs) are abundant in HR+ cancer, are highly immune-suppressive, associated with tumor progression, chemotherapy and ICB-resistance, metastasis and poor survival. We reveal novel therapeutic targets and possible combinations with ICB to enhance anti-tumor immune responses, which may have great potential in HR+ breast cancer.

Citing Articles

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References

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Tsujikawa T, Thibault G, Azimi V, Sivagnanam S, Banik G, Means C . Robust Cell Detection and Segmentation for Image Cytometry Reveal Th17 Cell Heterogeneity. Cytometry A. 2019; 95(4):389-398. PMC: 6461524. DOI: 10.1002/cyto.a.23726. View

Jaini R, Loya M, Eng C . Immunotherapeutic target expression on breast tumors can be amplified by hormone receptor antagonism: a novel strategy for enhancing efficacy of targeted immunotherapy. Oncotarget. 2017; 8(20):32536-32549. PMC: 5464807. DOI: 10.18632/oncotarget.15812. View

Munn D, Mellor A . IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol. 2016; 37(3):193-207. PMC: 4916957. DOI: 10.1016/j.it.2016.01.002. View

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G . The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2014; 26(2):259-71. PMC: 6267863. DOI: 10.1093/annonc/mdu450. View

Jackson H, Fischer J, Zanotelli V, Ali H, Mechera R, Soysal S . The single-cell pathology landscape of breast cancer. Nature. 2020; 578(7796):615-620. DOI: 10.1038/s41586-019-1876-x. View

Koletsa T, Kotoula V, Koliou G, Manousou K, Chrisafi S, Zagouri F . Prognostic impact of stromal and intratumoral CD3, CD8 and FOXP3 in adjuvantly treated breast cancer: do they add information over stromal tumor-infiltrating lymphocyte density?. Cancer Immunol Immunother. 2020; 69(8):1549-1564. PMC: 11027646. DOI: 10.1007/s00262-020-02557-0. View

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

Lee M, Heo S, Song I, Rajayi H, Park H, Park I . Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis. Mod Pathol. 2018; 32(1):70-80. DOI: 10.1038/s41379-018-0113-8. View

10.

Krishnamurti U, Wetherilt C, Yang J, Peng L, Li X . Tumor-infiltrating lymphocytes are significantly associated with better overall survival and disease-free survival in triple-negative but not estrogen receptor-positive breast cancers. Hum Pathol. 2017; 64:7-12. DOI: 10.1016/j.humpath.2017.01.004. View

11.

Wesolowski R, Sharma N, Reebel L, Rodal M, Peck A, West B . Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors. Ther Adv Med Oncol. 2019; 11:1758835919854238. PMC: 6589951. DOI: 10.1177/1758835919854238. View

12.

Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T . Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat. 2013; 12(3):259-67. DOI: 10.7785/tcrt.2012.500312. View

13.

Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman D, Xiao N . Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev. 2014; 23(12):2965-70. DOI: 10.1158/1055-9965.EPI-14-0654. View

14.

Schmid P, Adams S, Rugo H, Schneeweiss A, Barrios C, Iwata H . Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018; 379(22):2108-2121. DOI: 10.1056/NEJMoa1809615. View

15.

Barroso-Sousa R, Krop I, Trippa L, Tan-Wasielewski Z, Li T, Osmani W . A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. Clin Breast Cancer. 2020; 20(3):238-245. DOI: 10.1016/j.clbc.2020.01.012. View

16.

Anurag M, Zhu M, Huang C, Vasaikar S, Wang J, Hoog J . Immune Checkpoint Profiles in Luminal B Breast Cancer (Alliance). J Natl Cancer Inst. 2019; 112(7):737-746. PMC: 7805027. DOI: 10.1093/jnci/djz213. View

17.

Topalian S, Taube J, Anders R, Pardoll D . Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016; 16(5):275-87. PMC: 5381938. DOI: 10.1038/nrc.2016.36. View

18.

Szekely B, Bossuyt V, Li X, Wali V, Patwardhan G, Frederick C . Immunological differences between primary and metastatic breast cancer. Ann Oncol. 2018; 29(11):2232-2239. DOI: 10.1093/annonc/mdy399. View

19.

Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali H . Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2015; 6(7):5449-64. PMC: 4467160. DOI: 10.18632/oncotarget.3216. View

20.

Garrido F, Cabrera T, Aptsiauri N . "Hard" and "soft" lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int J Cancer. 2010; 127(2):249-56. DOI: 10.1002/ijc.25270. View