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1208.Full-Text.Pdf Published OnlineFirst June 19, 2019; DOI: 10.1158/2159-8290.CD-18-1454 RESEARCH ARTICLE Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Effi cacy in Triple-Negative Breast Cancer Jaclyn Sceneay 1 , 2 , Gregory J. Goreczny 1 , 2 , Kristin Wilson 1 , Sara Morrow 1 , Molly J. DeCristo 1 , 2 , Jessalyn M. Ubellacker1 , 2 , Yuanbo Qin 1 , 2 , Tyler Laszewski 1 , Daniel G. Stover 3 , Victor Barrera 4 , John N. Hutchinson 4 , Rachel A. Freedman 5 , 6 , Elizabeth A. Mittendorf 6 , 7 , and Sandra S. McAllister 1 , 2 , 8 , 9 ABSTRACT Immune checkpoint blockade (ICB) therapy, which targets T cell–inhibitory recep- tors, 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-infi ltrating 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 effi cacy 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 fi rst time that age determines the T cell–infl amed phenotype in TNBC and affects response to ICB in mice. Evaluating IFN-related genes from tumor genomic data may aid identifi cation of patients for whom combination therapy including an IFN pathway activator with ICB may be required. 1 Division of Hematology, Department of Medicine, Brigham and Women’s Note: Supplementary data for this article are available at Cancer Discovery Hospital, Boston, Massachusetts. 2 Department of Medicine, Harvard Online (http://cancerdiscovery.aacrjournals.org/). 3 Medical School, Boston, Massachusetts. Division of Medical Oncology, J. Sceneay and G.J. Goreczny contributed equally to this article. Ohio State University Comprehensive Cancer Center, Columbus, Ohio. 4 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Corresponding Author: Sandra S. McAllister, Harvard Medical School, Boston, Massachusetts. 5 Department of Medical Oncology, Dana-Farber Brigham & Women’s Hospital, 4 Blackfan Circle, HIM 742, Boston, MA Cancer Institute, Boston, Massachusetts. 6 Breast Oncology Program, 02115. Phone: 617-525-4929; Fax: 617-355-9093; E-mail: smcallister1@ Dana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts. bwh.harvard.edu 7 Division of Breast Surgery, Department of Surgery, Brigham and Cancer Discov 2019;9:1208–27 8 Women’s Hospital, Boston, Massachusetts. Broad Institute of Harvard and doi: 10.1158/2159-8290.CD-18-1454 MIT, Cambridge, Massachusetts. 9 Harvard Stem Cell Institute, Cambridge, Massachusetts. © 2019 American Association for Cancer Research. 1208 | CANCER DISCOVERY SEPTEMBER 2019 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst June 19, 2019; DOI: 10.1158/2159-8290.CD-18-1454 INTRODUCTION FDA approval of atezolizumab as first-line therapy for meta- static TNBC. ICB represents an improvement over standard Recent clinical successes using immune checkpoint block- therapeutic strategies for TNBC; however, the reasons that ade (ICB) have led to FDA approval of antibody-based ther- ICB therapy has had selected efficacy for patients with TNBC apeutics that target T cell–inhibitory receptors, including (14) are unknown. CTLA4, PD-1, and PD-L1. These therapies have revolution- Age is associated with increasing immune dysfunction that ized cancer treatment, particularly for melanoma and non– includes significant changes to both innate and adaptive immu- small cell lung cancer (NSCLC; refs. 1–5). Focus has recently nity (15–17). Most notably, hematopoiesis is skewed toward mye- shifted to applying ICB to other tumor types including breast loid production whereas lymphopoiesis retracts with age. Some cancer. Breast cancers that do not express hormone receptors of the age-related changes specific to peripheral T-cell popula- (estrogen receptor, progesterone receptor) and lack amplifi- tions include fewer naïve T cells, increased numbers of terminally cation of HER2 are classified as triple-negative breast cancer differentiated memory T cells, reduced expression of the costim- (TNBC), which lacks targeted therapy and is the most aggres- ulatory molecule CD28, and increased exhaustion, evidenced by sive subtype of the disease (6). Evaluation of ICB has been of PD-1 expression (18). Antigen-presenting cells including den- greatest interest in TNBC due to higher numbers of tumor- dritic cells (DC) and macrophages also have decreased activity, infiltrating lymphocytes (TIL) and elevated PD-L1 expression, whereas immunosuppressive populations, such as regulatory which correlate with response to ICB, relative to other breast T cells (Treg) and myeloid-derived suppressor cells (MDSC), have cancer subtypes (7–10). ICB monotherapy has proven effec- increased activity with age in patients with cancer (19). Although tive for approximately 10% of patients with TNBC (11, 12). most aspects of innate and adaptive immunity are different The IMpassion130 trial recently reported that patients with between young and elderly individuals, the clinical implications metastatic TNBC whose tumors express PD-L1 significantly of these age-related changes are unknown. benefited from anti–PD-L1 (atezolizumab) when administered Age-related immune dysfunction could therefore present with the chemotherapy nab-paclitaxel (13), leading to recent particular challenges to efficacy of immunotherapy in breast SEPTEMBER 2019 CANCER DISCOVERY | 1209 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst June 19, 2019; DOI: 10.1158/2159-8290.CD-18-1454 RESEARCH ARTICLE Sceneay et al. cancer, as more than 50% of patients are older than 60 years tumors grew similarly in young and aged BALB/c mice and of age at diagnosis (20). However, most clinical studies either McNeuA tumors grew more slowly in aged than in young FVB exclude or under-enroll older patients (21) and do not include mice (Supplementary Fig. S1C and S1D), suggesting that age- tissue-based analyses that can help predict for efficacy. Given related host physiology may affect tumor growth. the limited number of older patients enrolled on clinical We next assessed tumor-related changes to the peripheral trials evaluating ICB in TNBC, it is not known whether age immune system with age. Relative to cancer-free animals, cir- affects response to therapy. We therefore initiated a study in culating lymphocytes were reduced in young tumor-bearing murine models of TNBC to understand whether age-related mice, and this reduction was even more enhanced in aged immune dysfunction influences ICB efficacy in TNBC. tumor-bearing mice (Fig. 1G and H; Supplementary Fig. S1E). Young and aged tumor-bearing BALB/c and FVB mice exhib- RESULTS ited neutrophilia, which was more pronounced in the aged cohort than in the young cohort (Fig. 1I and J; Supplementary Age-Dependent Effects on Peripheral Immunity, Fig. S1F). In young BALB/c mice, we observed a reduction in TNBC Progression, and Tumor Immune circulating monocytes with tumorigenesis; however, in aged Microenvironment BALB/c mice, which already had lower monocyte counts, these To identify murine models correlating with age-associated levels were unchanged with tumorigenesis (Fig. 1K; Supple- immune changes seen in humans, we first assessed age- mentary Fig. S1G). In the FVB mice, neither age nor tumori- associated differences in peripheral immune cells from young genesis resulted in altered monocyte levels (Fig. 1L). (8–10 weeks) and aged (>12 months) BALB/c and FVB mice. We next examined the TME by IHC. There were no sig- Lymphocytes comprised the majority of circulating white nificant age-dependent differences in the percentage of Ki67+ blood cells (WBC) in both strains of mice, irrespective of age proliferating cells or myofibroblasts α( -SMA) in 4T1 or Met1 (Fig. 1A and B). However, total lymphocyte counts, includ- tumors (Supplementary Fig. S1H and S1I). Macrophage ing both CD4+ and CD8+ T cells, were significantly reduced (F4/80+) infiltration was significantly reduced in 4T1 tumors in both strains of aged mice compared with young mice from aged BALB/c mice relative to young, but unchanged in (Fig. 1A–D). The circulating myeloid cell compartment was Met1 tumors from FVB mice (Supplementary Fig. S1H and significantly expanded in both strains with age (Fig. 1A and S1I). We observed an increase in the overall percentage of B). Within the myeloid compartment, neutrophil counts intratumoral neutrophils (MPO+) in 4T1 tumors compared were elevated in both strains whereas monocyte counts were with Met1 tumors (Supplementary Fig. S1H and S1I), but altered in a strain-specific manner (Fig 1A and B). no difference when comparing young and aged mice in the Given that aged mice reflected
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