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Myocardial infarction accelerates breast cancer via innate immune reprogramming

Abstract

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3,4,5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6Chi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.

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Fig. 1: Surgically induced MI accelerates tumor growth in a syngeneic mouse model of breast cancer.
Fig. 2: MI-accelerated tumor growth is dependent on enhanced Ly6Chi monocyte supply and recruitment to tumors.
Fig. 3: Tumoral Ly6Chi mMDSCs exhibit an MI-induced immunosuppressive transcriptional phenotype that is epigenetically imprinted in bone marrow.
Fig. 4: MI accelerates cancer progression in mice and incident cardiovascular events increase the risk of recurrence and cancer-specific mortality in patients with early-stage breast cancer.

Data availability

All data generated are included in the article and in its Supplementary Information. Gene-expression data that support the findings of this study have been deposited in the Gene Expression Omnibus under accession number GSE137790. All data are also available from the corresponding authors on reasonable request.

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Acknowledgements

Tissue sectioning and histological analyses were provided by the New York University (NYU) Langone’s Experimental Pathology Research Laboratory. Cell sorting/flow cytometry technologies were provided by NYU Langone’s Cytometry and Cell Sorting Laboratory, which is supported in part by grant P30CA016087 from the National Institutes of Health/National Cancer Institute. This work was supported by funding from the National Institutes of Health (R35HL135799 to K.J.M., P01HL131478 and P01HL131481 to K.J.M. and E.A.F., T32HL098129 to C.v.S., K23HL125991 to J.D.N., R01CA234025 to E.R.N., R01CA129059 to B.J.C. and R01HL132073 to D.S.P.); NYU Cancer Institute Center Support Grant NCIP30CA16087; NYU Shared Instrumentation Grant S10 OD021747; the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748)), the American Heart Association (19CDA34630066 to C.v.S., 19POST34380010 to M.S., 18CDA34110203 to T.J.B. and 20POST35080180 to N.Y.), the Canadian Institutes of Health Research (Doctoral Foreign Study Award to G.J.K. and PJT159742 to D.F.Q.), AKTIV Against Cancer (L.W.J.) and the Susan G. Komen Foundation (CCR18548032 to D.F.Q.). D.F.Q. is also supported by the Brain Tumor Funders’ Collaborative, Canada Foundation for Innovation and a Tier II Canada Research Chair in tumor microenvironment research.

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Authors

Contributions

G.J.K., L.W.J. and K.J.M. conceptualized the study; G.J.K., A.A.C.N., E.M.C., C.v.S., M.S.A., M.S., M.S., L.S., T.J.B., K.R., N.Y., D.N. and V.M. performed investigative studies; E.J.B., K.A., J.D.N. and B.J.C. performed data analysis; L.W.J., E.A.F., D.S.P., D.F.Q. and E.R.N. provided input on study design and interpretation; K.J.M. supervised the study; G.J.K. and K.J.M. wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Kathryn J. Moore.

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Peer review information Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Cardiac function is not altered by the presence of cancer following surgical MI.

(a) Representative triphenyl-tetrazolium chloride (TTC) staining to confirm surgical myocardial infarction through ligation of the left anterior descending coronary artery. (b) Echocardiography examination 16 days following MI or sham surgery (19 days post tumor implantation). Values are mean ± SD. BW Body weight, LV area d, left ventricular area at diastole; LV area s, left ventricular area at systole; EF, ejection fraction; LV volume d, left ventricular volume at diastole; LV volume s, left ventricular volume at systole; SV, stroke volume; FS, longitudinal fractional shortening; CI, cardiac index; LVAWd, left ventricular anterior wall thickness at diastole; LVPWd, left ventricular posterior wall thickness at diastole; LV mass cor, left ventricular mass corrected. P values in data determined as non-parametric were analyzed by a two-tailed Mann–Whitney test, while data determined to be parametric were analyzed by a two-tailed unpaired Student’s t-test; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 for sham (no tumor vs tumor) and MI (no tumor vs tumor) comparisons only.

Extended Data Fig. 2 Proliferation of immune (CD45+) and non-immune (CD45-) cells in tumors of mice following MI or sham surgery.

Quantification of Ki67 and CD45 co-staining of tumors to detect proliferating CD45 a, and CD45+b, cells in the tumor border (n = 5/group). Data are the mean ± s.e.m and P values determined using a two-tailed unpaired Student’s t-test.

Extended Data Fig. 3 Flow cytometric analysis of intratumoral immune cells following MI or sham surgery.

a, Flow cytometry gating strategy for myeloid (top) and lymphoid (bottom) cells in E0771 tumors. b, Flow cytometric analysis showing the relative fold change in immune cell proportions in tumors from mice exposed to MI (n = 11, red) vs sham (n = 10, grey) surgery (day 20); two independent experiments were conducted. All populations were gated based on live/dead stain and CD45+. c, Flow cytometric analysis of CD11b+Gr1-Cd11c+ dendritic cell-like exposed to MI (n = 7) or sham (n = 7) surgery and CD11b+ Gr1+ F4/80+ macrophage-like cells in E0771 tumors from mice exposed to MI (n = 5) or sham (n = 4) surgery. d, Flow cytometric analysis of tumor immune cells (% total live cells) at day 20 to identify CD3+ T cells (n = 11 MI, 10 sham) and CD11b + myeloid (n = 14 MI, 11 sham) subsets: CD11b+ Ly6G+, neutrophils; CD11b+ Gr1, macrophage-like cells; CD11b+ Ly6Chi, monocytes; Data are the mean ± s.e.m and P values in data were analyzed by a two-tailed Mann–Whitney test (b [FoxP3+ cells]), or a two-tailed unpaired Student’s t-test (b,c,d).

Extended Data Fig. 4 Circulating leukocytes and bone marrow progenitors in tumor bearing mice following MI or sham surgery.

a, Numbers of circulating leukocytes and relative proportion of neutrophils, eosinophils, lymphocytes and basophils in E0771 tumor bearing mice after MI (n = 8) or sham (n = 8) surgery. b,c, Flow cytometric analysis of bone marrow hematopoietic and stem cell populations in E0771 tumor bearing mice 9 days post-MI or sham surgery (12 days post-tumor cell implantation). LSK: LineageSca1cKit+ cells; CMP: common myeloid progenitor; GMP: granulocytic myeloid progenitor; MEP: megakaryocyte–erythroid progenitor. (a-c) two independent experiments were conducted. Data are the mean ± s.e.m. P values were calculated using a two-way analysis of variance (ANOVA), with results not significant (p > 0.05) (a), or a two-tailed unpaired Student’s t-test (c).

Extended Data Fig. 5 Monocyte adoptive transfer experiments into tumor bearing mice; RNA-seq analyses of tumor and bone marrow monocytes in mice exposed to MI or sham surgery.

ac, Monocytes were adoptively transferred from CD45.1 mice 9 days after exposure to MI or sham surgery into E0771 tumor bearing CD45.2 mice (a), and tumor weight (b), and CD45.1 Ly6Chi monocytes recruited to the tumor (c) were determined 16 h later (n = 9 sham; n = 8 MI). de, Monocytes were adoptively transferred from CD45.1 mice into E0771 tumor-bearing CD45.2 mice 9 days following MI or sham surgery (d), and tumor weight was determined 16 h later (n = 9 sham; n = 10 MI) (e). f, Fold change (FC) in gene expression in E0771 tumors from mice 8 days post-MI compared to sham surgery (n = 3 per group). g, Heatmap of genes significantly up- or down-regulated (p < 0.05, two-sided Wald test) in bone marrow monocytes 9-10 days after MI vs sham treatment specifically in tumor bearing mice. MI (n = 6, 3 pools of 2 mice), sham (n = 10, 5 pools of 2 mice), MI + tumor (n = 5), or sham+tumor (n = 6). (a-e) two independent experiments were conducted. Data are the mean ± S.D. and P values were analyzed by two-tailed unpaired Student’s t-test (b, c, e, f), with comparisons not significant unless indicated. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.

Extended Data Fig. 6 CCR2 inhibition mitigates MI-induced accelerated tumor growth.

a, Outline of CCR2 inhibition study in mice implanted with E0771 tumor cells and exposed to MI or sham surgery. CCR2 inhibitor (CCR2i) was administered starting at 7 days after MI or sham surgery. b, Tumor volume over the course of the study (left) and at sacrifice (day 20 day) (right) in mice exposed to MI (n = 5 CCR2 inhibitor, n = 7 DMSO control) or sham surgery (n = 8 CCR2 inhibitor, n = 7 DMSO control). Two independent experiments were conducted (a-c). P values were calculated using a repeated measures analysis of variance (ANOVA) with Bonferroni’s multiple comparisons test (b) or one way ANOVA (c).

Extended Data Fig. 7 Monocytic myeloid-derived suppressor cells isolated from tumors of mice exposed to MI or sham surgery do not alter the proliferation of T cells in vitro.

a, Representative flow plots of CD11b-Ly6C-CD8+ T cells from MDSC:T cell suppression assay, representing % IFN𝛾+, TNFα+, Granzyme B (GrB)+ populations. b,c, Purified splenic CD8+ T cells from naïve mice were stimulated with αCD3/αCD28 for 72 hours in the presence of mMDSCs isolated from tumors from mice exposed to MI (n = 5) or sham surgery (n = 7), and CD8+ T cell proliferation was assessed by % Ki67 (b) and replication and division index (c) using a cell trace proliferation dye. (a,b,c) two independent experiments were conducted. Data are the mean ± s.e.m. P values were calculated using or two-tailed unpaired Student’s t-test (b,c), where relevant comparisons were not significant (p > 0.05).

Extended Data Fig. 8 RNA-seq and ATAC-seq analyses of mMDSCs in tumor and bone marrow of mice exposed to MI or sham surgery.

a, Heat map showing differential gene expression (log2FC) of select immune-related genes from RNA-Seq of tumoral CD11b+ Ly6Chigh mMDSCs from mice 17 days post-MI (n = 5) or sham (n = 6) surgery (Padj < 0.1). b, Gene set concordance analysis showing that the top 1000 differentially expressed genes up- and down-regulated in tumor CD11b + Ly6Chigh mMDSCs (x axis) are enriched in genes up- and down-regulated in bone marrow Ly6Chigh monocytes (y axis) from the same mice 17 days post-MI, compared to background gene expression. c, Gene ontology (GO) analyses of more accessible chromatin regions (n = 942) in bone marrow Ly6Chigh monocytes from mice exposed to MI vs. sham surgery. d, List of genes differentially expressed in tumor Ly6Chigh monocytes whose chromatin loci that are also less accessible in bone marrow Ly6Chigh monocytes after MI compared to sham surgery, grouped by transcription factors identified in Fig. 3e. e, ATAC-Seq (top) and RNA-Seq (bottom) reads in bone marrow and tumor Ly6Chigh monocytes at selected gene loci. P(adj) values were calculated using the Benjamini-Hochberg method (a). P values determined by two-sided Student’s T-test (b) or hypergeometric distribution (c).

Extended Data Fig. 9 The effect of systemic CD8+ cell depletion on tumor growth in mice following MI or sham surgery.

a, E0771 tumor-bearing mice were exposed to MI or sham surgery and randomly allocated to either intraperitoneal IgG or anti-CD8 injections 10, 15, and 19 days following tumor implantation. b, Intratumoral T cell content measured by flow cytometry in sham+IgG (n = 8), sham+anti-CD8 (n = 7), MI + IgG (n = 8) and MI + anti-CD8 (n = 9). c, Tumor volume was followed over 20 days and at sacrifice (d) in sham+IgG (n = 8), sham+anti-CD8 (n = 7), MI + IgG (n = 8) and MI + anti-CD8 (n = 7). ad, two independent experiments were conducted. Data are the mean ± s.e.m. P values were calculated using a repeated measures analysis of variance (ANOVA) with Bonferroni’s multiple comparisons test (c) or a two-tailed (b) or one-tailed (d) Mann–Whitney test.

Extended Data Fig. 10 Tumor growth, circulating monocytes and intratumoral innate immune flow cytometry gating strategy in MMTV-PyMT mice following surgical MI or sham surgery.

a, Mean tumor volume at time of MI (n = 8) or sham surgery (n = 8) in MMTV-PyMT mice. b, Tumor growth in MMTV-PyMT mice after MI or sham surgery (n = 8/group). c, Tumor volume at sacrifice in MMTV-PyMT mice used for the metastasis subgroup analysis (n = 4/group). d, Circulating monocytes in MMTV mice exposed to MI or sham surgery (n = 8/group). e, Flow cytometry gating strategy for myeloid cells from MMTV-PyMT tumors. Mammary tissue macrophages (MTM: CD11bhighMHCII+); granulocytic myeloid derived suppressor cell (gMDSC: CD11bhighMHCII-Ly6CloLy6Ghigh); monocytic myeloid derived suppressor cell (mMDSC: CD11bhighMHCII-Ly6ChiLy6Glo); tumor-associated macrophage (TAM: CD11bloMHCIIhigh). (a-e) three independent experiments were conducted. Data are the mean ± s.e.m and P values were calculated using a repeated measures analysis of variance (ANOVA) (d) with Bonferroni’s multiple comparisons test (b) or by a two-tailed unpaired Student’s t-test (a, c).

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Koelwyn, G.J., Newman, A.A.C., Afonso, M.S. et al. Myocardial infarction accelerates breast cancer via innate immune reprogramming. Nat Med 26, 1452–1458 (2020). https://doi.org/10.1038/s41591-020-0964-7

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