Highlights
- •High levels of TILs are associated with higher PFS and OS in TNBC.
- •About 15% of TNBC patients presents high levels of TILs at diagnosis.
- •In low TILs group, higher expression of CTLA-4 in local lymph nodes of TNBC was observed.
- •Higher neoantigen load and expression of B7.H3 and B7.H4 were observed in low TIL tumours.
- •In high TILs, more PD-L1+ tumour cells and more expanded humoral response were observed.
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with unmet medical
needs. Several studies have proved that high levels of tumor infiltrating lymphocytes
(TILs) at diagnosis of TNBC confer better prognosis and patients respond better to
specific chemotherapies. Nonetheless, current evidence suggests that only 15% of TNBC
patients have very high levels of TILs, and another 15% lacks TILs. One possible reason
to explain why patients have low TILs at diagnosis is that lymphocytes might be deactivated
by an immune checkpoint in local lymph nodes, provoking their retention in there as
they are unresponsive to other immune stimuli.
We have identified 15 high TILs (≥50%) and 20 low TILs (≤5%) TNBC patients with localised
tumour (T1c-T2N0M0) and compared the protein expression of five immune checkpoints
in lymph nodes. We have also performed a customised 50-immune gene NanoString expression
panel, the NanoString 360 Breast Cancer panel, and whole exome sequencing for mutation
and neoantigen load analyses.
In low TILs, we observed higher expression of CTLA-4 in local lymph nodes, which could
explain why lymphocytes get retained in there and do not migrate to tumour. These
patients have also higher neoantigen load and higher expression of B7.H3 and B7.H4
in the tumour. In high TILs, we observed more PD-L1+ tumour cells and more expanded
humoral response. These results could provide a strategy to revert low tumour immune
infiltration at diagnosis of TNBC, improving their prognosis.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.N Engl J Med. 2018; 379: 2108-2121
- Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2019; 1: 44-59
- KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer.J Clin Oncol. 2020; 38: 1000
- Pembrolizumab for early triple-negative breast cancer.N Engl J Med. 2020; 382: 810-821
- Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.J Clin Oncol. 2013; 31: 860-867
- 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: 1544-1550
- Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers.J Clin Oncol. 2019; 37: 559-569
- Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.J Clin Oncol. 2010; 28: 105-113
- Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer.Breast Cancer Res. 2011; 13: R126
- 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: 983-991
- Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial.PloS One. 2013; 8e79775
- 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: 2959-2966
- Abstract S1-03: pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy.Canc Res. 2016; 76 (Abstract nr): S1-S03
- Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review.JAMA Oncol. 2016; 2: 1354-1360
- Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer.PLoS Med. 2005; 2: e284
- Morphology of immunomodulation in breast cancer tumor draining lymph nodes depends on stage and intrinsic subtype.Sci Rep. 2018; 8: 5321
- Analysis of dendritic cells in tumor-free and tumor-containing sentinel lymph nodes from patients with breast cancer.Breast Cancer Res. 2004; 6: R408-R415
- Immunohistochemical analysis of primary breast tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule OX-40.Am J Surg. 2000; 179: 400-406
- Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immunooncology biomarkers working group: Part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research.Adv Anat Pathol. 2017; 24: 235-251
- Clinicopathological correlation of PD-L1 expression in primary and metastatic breast cancer and infiltrating immune cells.Hum Pathol. 2018; 80: 170-178
NanoString Technologies. nCounter® Breast Cancer 360TM Panel. Available at: https://www.nanostring.com/products/gene-expression-panels/gene-expression-panels-overview/ncounter-breast-cancer-360-panel. [Accessed 8 July 2020].
- Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.Nat Biotechnol. 2013; 31: 213-219
- NetMHCpan-4.0: improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data.J Immunol. 2017; 199: 3360-3368
- pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens.Genome Med. 2016; 8: 11
- Advances in cancer immunotherapy 2019 - latest trends.J Exp Clin Canc Res. 2019; 38: 268
- B7-H3 and B7-H4 expression in breast cancer and their association with clinicopathological variables and T cell infiltration.Pathobiology. 2020; 87: 179-192
- New B7 family checkpoints in human cancers.Mol Canc Therapeut. 2017; 16: 1203-1211
- Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival.OncoImmunology. 2018; 7e1509820
- MHC/HLA class I loss in cancer cells.Adv Exp Med Biol. 2019; 1151: 15-78
- Association between genomic metrics and immune infiltration in triple-negative breast cancer.JAMA Oncol. 2017; 3: 1707-1711
- Tumor-infiltrating lymphocyte composition, organization and PD-1/PD-L1 expression are linked in breast cancer.OncoImmunology. 2016; 6e1257452
- Systemic immunity is required for effective cancer immunotherapy.Cell. 2017; 168: 487-502
- Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy.Lancet Oncol. 2018; 19: 40-50
Article info
Publication history
Published online: March 17, 2021
Accepted:
January 28,
2021
Received in revised form:
January 26,
2021
Received:
December 10,
2020
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
