Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer.

Jaclyn Sceneay,Sara Morrow,Rachel A Freedman,John N Hutchinson,Kristin Wilson,Sandra S Mcallister,Jessalyn M Ubellacker,Molly J Decristo,Elizabeth A Mittendorf,Victor Barrera,Yuanbo Qin,Gregory J Goreczny,Daniel G Stover,Tyler Laszewski

doi:10.1158/2159-8290.cd-18-1454

Abstract

Immune checkpoint blockade (ICB) therapy, which targets T cell-inhibitory receptors, has revolutionized cancer treatment. Among the breast cancer subtypes, evaluation of ICB has been of greatest interest in triple-negative breast cancer (TNBC) due to its immunogenicity, as evidenced by the presence of tumor-infiltrating lymphocytes and elevated PD-L1 expression relative to other subtypes. TNBC incidence is equally distributed across the age spectrum, affecting 10% to 15% of women in all age groups. Here we report that increased immune dysfunction with age limits ICB efficacy in aged TNBC-bearing mice. The tumor microenvironment in both aged mice and patients with TNBC shows decreased IFN signaling and antigen presentation, suggesting failed innate immune activation with age. Triggering innate immune priming with a STING agonist restored response to ICB in aged mice. Our data implicate age-related immune dysfunction as a mechanism of ICB resistance in mice and suggest potential prognostic utility of assessing IFN-related genes in patients with TNBC receiving ICB therapy. SIGNIFICANCE: These data demonstrate for the first time that age determines the T cell-inflamed phenotype in TNBC and affects response to ICB in mice. Evaluating IFN-related genes from tumor genomic data may aid identification of patients for whom combination therapy including an IFN pathway activator with ICB may be required.This article is highlighted in the In This Issue feature, p. 1143.

Highlights

Recent clinical successes using immune checkpoint blockade (ICB) have led to FDA approval of antibody-based therapeutics that target T cell–inhibitory receptors, including CTLA4, PD-1, and PD-L1
Lymphocytes comprised the majority of circulating white blood cells (WBC) in both strains of mice, irrespective of age (Fig. 1A and B)
Given that aged mice reflected the myeloid bias and decreased lymphocyte production observed in humans with age [22,23,24], we proceeded to test whether age affects tumor progression and development of the tumor microenvironment (TME)

Summary

Introduction

Recent clinical successes using immune checkpoint blockade (ICB) have led to FDA approval of antibody-based therapeutics that target T cell–inhibitory receptors, including CTLA4, PD-1, and PD-L1. These therapies have revolutionized cancer treatment, for melanoma and non– small cell lung cancer Focus has recently shifted to applying ICB to other tumor types including breast cancer. Evaluation of ICB has been of greatest interest in TNBC due to higher numbers of tumorinfiltrating lymphocytes (TIL) and elevated PD-L1 expression, which correlate with response to ICB, relative to other breast cancer subtypes [7,8,9,10]. The IMpassion130 trial recently reported that patients with metastatic TNBC whose tumors express PD-L1 significantly benefited from anti–PD-L1 (atezolizumab) when administered with the chemotherapy nab-paclitaxel [13], leading to recent

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