Abstract
Doxorubicin, the most prescribed chemotherapeutic drug, causes dose-dependent cardiotoxicity and heart failure. However, our understanding of the immune response elicited by doxorubicin is limited. Here we show that an aberrant CD8+ T cell immune response following doxorubicin-induced cardiac injury drives adverse remodeling and cardiomyopathy. Doxorubicin treatment in non-tumor-bearing mice increased circulating and cardiac IFNγ+CD8+ T cells and activated effector CD8+ T cells in lymphoid tissues. Moreover, doxorubicin promoted cardiac CD8+ T cell infiltration and depletion of CD8+ T cells in doxorubicin-treated mice decreased cardiac fibrosis and improved systolic function. Doxorubicin treatment induced ICAM-1 expression by cardiac fibroblasts resulting in enhanced CD8+ T cell adhesion and transformation, contact-dependent CD8+ degranulation and release of granzyme B. Canine lymphoma patients and human patients with hematopoietic malignancies showed increased circulating CD8+ T cells after doxorubicin treatment. In human cancer patients, T cells expressed IFNγ and CXCR3, and plasma levels of the CXCR3 ligands CXCL9 and CXCL10 correlated with decreased systolic function.
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Acknowledgements
We thank the Tufts University Histology Core, Flow Cytometry Core, and CMS Animal Facility for their support in this work. We also thank our collaborators at Beth Israel Deaconess Medical Center (BIDMC) and Colorado State University (CSU) and the support of their institutions. We would also like to acknowledge S. Sharma, from Tufts University School of Medicine, for the use of the microscope to image full heart cross-section. All graphic figures were created with BioRender.com. This work was supported by National Institute of Health (NIH) grants R01 HL144477 and HL165725 (P.A.), Tufts Springboard Tier 1 grant (P.A. and C.L.), American Heart Association (AHA) Pre-Doctoral Fellowship 906361 (A.L.B.), NIH F30 grant HL162200 (A.L.B.), NIH 3R01HL144477-04S1 grant (M.A.Z.), NIH F31 grant HL159907A (S.S.), AHA Pre-Doctoral grant 906561 (S.S.), NIH U01CA272268 (C.L. and A. Avery), NIH K08HL145019 (A. Asnani) and NIH R01 HL163172 (A. Asnani).
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A.L.B. designed the project, performed experiments, analyzed data, and wrote the manuscript. M.A.Z., S.S., Z.L.R. and M.S. performed experiments, provided intellectual support and edited the paper. K.K. provided intellectual and technical support and edited the paper. A. Ariza and A. Asnani recruited human patients and assisted in collecting patient data, provided intellectual support and edited the paper. A. Avery and C.L. recruited and treated canine patients, collected and analyzed flow cytometry data and provided intellectual support. P.A. designed the project, provided intellectual support and contributed to writing and editing the manuscript.
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Extended data
Extended Data Fig. 1 Doxorubicin Effects on Cardiac and Circulating Myeloid Populations.
WT mice were treated with PBS or 5.0 mg/kg DR for 4 or 8 weeks (n = 7–10 mice / group). A. Hearts were digested and analyzed by flow cytometry, shown is the gating strategy used for T-cells and myeloid populations, and quantification by frequency or total cell number for CD11b+ cells (B,F), CD11b+CCR2+ cells (C,G), CD11b+Ly6G- cells (D,H), or CD11b+MertK+ cells (E, I). J. Whole blood was analyzed by flow cytometry, shown is gating strategy for T-cells and myeloid populations, and quantification for CD11b+CCR2+ cells (K), or CD11b+Ly6G- cells (L). All data shown are mean±SEM. Statistical analysis by 2-way ANOVA with Sidak’s multiple comparison test, exact p-values shown.
Extended Data Fig. 2 Female Mice Treated with Doxorubicin Exhibit Cardiotoxicity and Cardiac CD8+ T-cell Infiltration.
A. Schematic of DR treatment in female mice (n = 7 mice / group). B-C. Echocardiography was used to measure ejection fraction and wall thickness one day prior to tissue collection. D. Whole heart weight normalized to tibia length. E-F. Formalin fixed cardiac samples were stained with TUNEL, representative images shown in E with scale bars of 50 μm quantified using ImageJ in F. G-J. Hearts were enzymatically and mechanically digested and analyzed for cardiac T-cells by flow cytometry (gating strategy in Supplementary Fig. 1). Quantification by frequency shown in G, I and by total cell number in H, J. K-L. Whole blood was analyzed by flow cytometry for circulating T-cells (gating strategy in Supplementary Fig. 1) quantified in K-L. All data shown are mean±SEM. Statistical analysis by 2 sided T-tests, exact p-values shown.
Extended Data Fig. 3 Gating Strategies for Lymphoid Organ Effector Populations.
WT mice were treated with PBS or 5.0 mg/kg DR for 4 or 8 weeks (n = 7–10 mice / group). A. Mediastinal lymph nodes or spleens were digested and analyzed by flow cytometry. Shown is gating strategy for effector and memory T-cells. B–E. Quantification of memory CD8+ T-cells by frequency (B,D) and total number (C,E) in the mLN and spleen. F. Representative plots for CD4+ effector T-cells from 8 week treated mice (gated on CD45+CD11b-CD4+ cells), with quantification for mLN (G-H) or splenic T-cells (I-J). K-N. Quantification of mLN and splenic effector CD8+ T-cells from female mice treated with DR for 4 weeks. All data shown are mean±SEM. Statistical analysis by 2-way ANOVA with Sidak’s multiple comparison test (B-J) or unpaired 2 sided T-test (K-N), exact p-values shown
Extended Data Fig. 4 Lymphoid T-cells Do Not Increase Exhaustion Markers in Response to Doxorubicin.
WT mice were treated with PBS or 5.0 mg/kg DR for 4 or 8 weeks (n = 7–9 mice per group), and mediastinal lymph nodes or spleens were digested and analyzed by flow cytometry. A. Gating strategy for T-cell PD-1 and CTLA-4 expression. B-C Quantification of relative mLN CD4+ T-cell PD-1 and CTLA-4 expression, with representative plots shown in D-E. F-G. Quantification of relative mLN CD8+ T-cell PD1 and CTLA-4 expression. H-I. Quantification of relative splenic CD4+ T-cell PD-1 and CTLA-4 expression. J-K. Quantification of relative splenic CD8+ T-cell PD-1 and CTLA-4 expression. All data shown are mean±SEM. Statistical analysis by 2-way ANOVA with Sidak’s multiple comparison test, exact p-values shown.
Extended Data Fig. 5 Doxorubicin Increases Multiple Helper T-cell Subtypes in Lymphoid Organs.
A. Schematic showing helper T-cell differentiation and transcription factors probed to quantify each subtype (n = 7–9 mice / group). B. Gating strategy used to identify T-cell transcription factors in digested mediastinal lymph nodes (mLN) or spleens form PBS or DR-treated mice, with quantification of mLN Th17 cells (C), mLN Th2 cells (D), splenic Th17 cells (E), or splenic Th2 cells (F). G. Representative plots of splenic CD4+ Tbx21 staining from 8 week treated mice (gated on CD45+CD11b-CD4+ cells), with quantification for splenic Th1 cells (H) or mLN Th1 cells (I). All data shown are mean±SEM. Statistical analysis by 2-way ANOVA with Sidak’s multiple comparison test, exact p-values shown.
Extended Data Fig. 6 Analysis of Doxorubicin Treatment in Antibody Depleted Mice.
WT mice were treated with Doxorubicin alongside anti-CD4 and anti-CD8 antibody depletion (see Fig. 4, n = 6 mice / group). A–C. mLN were digested and analyzed by flow cytometry, representative plots shown in A with quantified CD4+ T-cells (B) or CD8+ T-cells (C). D-F. Spleens were digested and analyzed by flow cytometry, representative plots shown in D with quantified CD4+ T-cells (E) or CD8+ T-cells (F). G-H. Cardiac sections were stained with wheat-germ agglutinin to measure cardiomyocyte area, representative images in G with scale bars of 50 μm, quantified using ImageJ in H. I-J. Cardiac sections were stained with anti-CD8 and analyzed by immunofluorescence, representative image identifying CD8+ T-cells shown in I. T-cells were counted manually and quantified in J. All data shown are mean±SEM. Statistical analysis by 1-way ANOVA with Tukey’s multiple comparison test, ns = no significance, exact p-values shown.
Extended Data Fig. 7 Analysis of Doxorubicin Treatment in Antibody Depleted Mice Cont.
A–C. WT mice were treated with Doxorubicin for 4 or 8 weeks (n = 7–9 mice / group), mLN were digested and analyzed by flow cytometry, (gating strategy in Supplementary Fig. 6). A. Frequency of Foxp3+CD4+ T-cells. B. Relative intensity of Helios expression in Foxp3+CD4+ T-cells, with representative plots for Helios staining in C. D-I. WT mice were treated with Doxorubicin alongside CD4 and CD8 antibody depletion (see Fig. 4, n = 6 mice / group). D-E. Cardiac sections were stained with TUNEL, representative images in D. with scale bars of 50 μm, quantified using ImageJ in E. F-G. Cardiac lysate was analyzed by western blotting for cleaved caspase 3, representative blot for n = 3 mice shown in F. quantified for n = 6 mice in G. H-I Cardiac sections were stained with picrosirius red, representative images in h. with scale bars of 50 μm, quantified using imageJ in I. All data shown are mean±SEM. Statistical analysis by 2 sided T-test (A-B), or 1-way ANOVA with Tukey’s multiple comparison test (E-I), exact p-values shown.
Extended Data Fig. 8 Tcra−/− mice Are Partially Protected from Doxorubicin Cardiomyopathy.
Age matched WT or Tcra−/− mice were treated with DR or PBS for 4 weeks (n = 6–8 mice / group). A-B. Echocardiography was used to measure ejection fraction and wall thickness one day prior to tissue collection. C. Whole heart weight normalized to tibia length. D. Frozen cardiac samples were stained with Wheat Germ Agglutinin (WGA), representative images shown in D with scale bars of 50 μm quantified using ImageJ in E-F. G-H. Formalin fixed cardiac samples were stained with TUNEL, representative images shown in G with scale bars of 50 μm quantified using ImageJ in H (TCR samples compared to 4w WT from Fig. 1). I-K. Cardiac lysate from PBS or 8w DR treated mice was analyzed by western blot for SERCA or IsoLG expression, representative blots for n = 3 mice show in I with quantification from n = 6 mice in J-K. L. Cardiac RNA was analyzed by RT-qPCR for alpha and beta myosin. M. Frozen cardiac samples were stained with DCFDA, representative images shown in M. with scale bars of 50 μm quantified using ImageJ in N-O. All data shown are mean±SEM. Statistical analysis by 2-way ANOVA with Sidak’s multiple comparison test.
Extended Data Fig. 9 Adoptive Transfer of Tc1 Cells Restores Doxorubicin Cardiotoxicity.
A. Schematic of DR treatment in Tcra−/− mice alongside adoptive transfer of Tc1 cells (n = 6 mice / group). B-C. Echocardiography was used to measure ejection fraction and wall thickness one day prior to tissue collection. D. Whole heart weight normalized to tibia length. E. Gating strategy for identification of CD8+ T-cells in the heart of lymphoid organs. Quantification of CD8+ T-cell number in the mediastinal lymph nodes (F), spleen (G), or heart (H). I-L. Formalin fixed cardiac samples were stained with picrosirius red, representative images shown in I/K. with scale bars of 50 μm quantified using ImageJ in the interstitial region (J), or perivascular region (L). m-n. Formalin fixed cardiac samples were stained with TUNEL, representative images shown in M. with scale bars of 50 μm quantified using ImageJ (N). All data shown are mean±SEM. Statistical analysis by 2 sided T-tests, exact p-values shown.
Extended Data Fig. 10 Gating Strategy for Patient Blood, Human T-cell Granzyme B Expression.
Whole blood was analyzed by flow cytometry from canine or human patients before or after anthracycline initiation. A. Gating strategies for T-cells from canine patients. B. Gating strategies for T-cells and additional markers from human patients. C. Representative plots for CD8 T-cell Granzyme B expression (gated on CD45+CD3+CD8+ cells), with quantification in D. Data from n = 5 patients shown paired before/after treatment. Statistical analysis by paired 2 sided T-test, p-value shown.
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Bayer, A.L., Zambrano, M.A., Smolgovsky, S. et al. Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction. Nat Cardiovasc Res 3, 970–986 (2024). https://doi.org/10.1038/s44161-024-00507-y
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DOI: https://doi.org/10.1038/s44161-024-00507-y
