An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers

Research output: Contribution to journalArticle

Abstract

Background: Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. Methods: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis. Results: The presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome. Conclusions: Overall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.

Original languageEnglish
Article number121
JournalBreast Cancer Research
Volume18
Issue number1
DOIs
Publication statusPublished - Dec 3 2016

Fingerprint

Triple Negative Breast Neoplasms
Tumor-Infiltrating Lymphocytes
Lymphocytes
Tumor Microenvironment
Survival
Anthracyclines
Lymphocyte Subsets
Hematoxylin
Eosine Yellowish-(YS)
Paraffin
Formaldehyde
Biomarkers
T-Lymphocytes
Recurrence
Drug Therapy

Keywords

  • Immune checkpoints
  • LAG-3
  • Prognosis
  • Triple-negative breast cancer
  • Tumor-infiltrating lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{fa4b0cd2fbc24d07a411dbcf548c3a7a,
title = "An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers",
abstract = "Background: Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. Methods: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis. Results: The presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15{\%} of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome. Conclusions: Overall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.",
keywords = "Immune checkpoints, LAG-3, Prognosis, Triple-negative breast cancer, Tumor-infiltrating lymphocytes",
author = "Giulia Bottai and Carlotta Raschioni and Agnese Losurdo and {Di Tommaso}, Luca and Corrado Tinterri and Torrisi, {Rosalba Maria Concetta} and Reis-Filho, {Jorge S.} and Massimo Roncalli and Christos Sotiriou and Armando Santoro and Alberto Mantovani and Sherene Loi and Libero Santarpia",
year = "2016",
month = "12",
day = "3",
doi = "10.1186/s13058-016-0783-4",
language = "English",
volume = "18",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers

AU - Bottai, Giulia

AU - Raschioni, Carlotta

AU - Losurdo, Agnese

AU - Di Tommaso, Luca

AU - Tinterri, Corrado

AU - Torrisi, Rosalba Maria Concetta

AU - Reis-Filho, Jorge S.

AU - Roncalli, Massimo

AU - Sotiriou, Christos

AU - Santoro, Armando

AU - Mantovani, Alberto

AU - Loi, Sherene

AU - Santarpia, Libero

PY - 2016/12/3

Y1 - 2016/12/3

N2 - Background: Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. Methods: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis. Results: The presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome. Conclusions: Overall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.

AB - Background: Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. Methods: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis. Results: The presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome. Conclusions: Overall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.

KW - Immune checkpoints

KW - LAG-3

KW - Prognosis

KW - Triple-negative breast cancer

KW - Tumor-infiltrating lymphocytes

UR - http://www.scopus.com/inward/record.url?scp=84999862825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84999862825&partnerID=8YFLogxK

U2 - 10.1186/s13058-016-0783-4

DO - 10.1186/s13058-016-0783-4

M3 - Article

AN - SCOPUS:84999862825

VL - 18

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 121

ER -