Abstract
Tumors poorly infiltrated by T cells are more resistant to immunogenic chemotherapies and checkpoint inhibition than highly infiltrated tumors. Using murine models, we found that CCR6+ type 3 innate lymphoid cells (ILC3s) can trigger an increase in the number of T cells infiltrating a tumor. Shortly after administration of cisplatin chemotherapy, production of the chemokine CCL20 and proinflammatory cytokine IL-1β at the tumor site led to the recruitment and activation of ILC3s. Within the tumor, ILC3 production of the chemokine CXCL10 was responsible for the recruitment of CD4+ and CD8+ T lymphocytes to the tumor. ILC3-dependent infiltration of T cells was essential for antitumor immune responses and increased the efficacy of checkpoint inhibition. Thus, we reveal an essential role of CCL20 and IL-1β, which promote ILC3-dependent antitumor immunity and enhance tumor sensitivity to immunotherapy.
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Data availability
The RNA-seq data generated in this paper have been deposited in the Gene Expression Omnibus database under accession number GSE171656. All other data needed to evaluate the conclusions in the paper are reported in the article or source data files. Source data are provided with this paper.
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Acknowledgements
We thank T.C. Wu (Johns Hopkins School of Medicine, Baltimore, MD) for providing TC-1 cells. This work was supported by the Association pour la Recherche sur le Cancer (M.B. and F.G.), an ISITE-BFC senior fellowship (F.G.), LabEx LipSTIC (Lipoprotéines et Santé) grant ANR-11-LABX0021 (F.G.), Ligue Contre Le Cancer CCIR EST (F.V.,M.B. and F.G.) and the Fondation de France (M.B.). F.G.’s team is supported by Equipe labélisée Ligue Nationale Contre le Cancer.
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M.B. contributed to conceptualization, investigation, visualization, writing and funding acquisition. M.G. contributed to investigation and validation. R.B., A.P., C.H., E. Barsac, C. Racoeur and F.C., C. Paul, C. Rébé contributed to investigation. E. Ballot and C.T. contributed to formal analysis. B.R., T.B. and C. Paget contributed resources. F.V. supervised the study and acquired funding. F.G. supervised the study and contributed to funding acquisition, conceptualization and writing.
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F.G. received honoraria for oral communication from Lilly, Sanofi, BMS, Astra Zeneca and Amgen; received funding for clinical trials by Astra Zeneca; received a travel grant from Roche France, Amgen and Servier; and is an advisory board member for Merck Serano, Amgen, Roche France and Sanofi. All other authors have no competing interests.
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Nature Immunology thanks Kingston Mills, Shigeo Koyasu and Cyril Seillet for their contribution to the peer review of this work. Zoltan Fehervari 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 Cisplatin induced immune recruitment to the poorly immune infiltrated cancer TC-1 model.
Therapeutic response of WT mice bearing a a, TC-1 n = 7, b, MC38, n = 5 and c, 4T1 n = 10 tumors treated with ICB on days 10-12-14, reflected by tumor growth kinetics. d, Therapeutic response of WT mice bearing urethane induced lung tumors treated with α-PD-L1, as reflected by the number of tumor foci. n = 9, results are shown as mean ± SEM. Flow cytometry analysis of e, CD45+ cells and f, CD4+ cells and CD8+ cells from TC-1, 4T1, urethane carcinogen induced model and MC38 used as positive control untreated tumors. Results show a number of cells for 300 000 total viable cells from each tumor, n = 5. g–n Flow cytometry analysis of immune cells infiltrating TC-1 tumors of WT mice treated with CDDP. Tumors were harvested and analyzed one, three or seven days after CDDP. Results show the numbers of cells from 300 000 total viable cells from each tumor. n = 5. Numbers of g, CD45+ cells. h, CD8+ cells. i, CD4+ cells. j, B cells. k, CD11c+ cells. l, CD11b+ cells. m, Myeloid-derived suppressor cells (MDSCs). n, TCRγδ+ cells. o–p two-dimensional tSNE representation of ILCs separated in 5 clusters from TC-1 tumors of WT mice treated with CDDP. Tumors were harvested and analyzed one, three or seven days after CDDP, n = 5. o, tSNE from all sequenced cells or p, separated by time points. Results are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using two tailed multiple unpaired T Test (a–c), two tailed unpaired T test (d), one-way anova (e) and two-way anova and Tukey’s multiple comparison test (f–n).
Extended Data Fig. 2 Gating strategies.
Gating strategies of flow cytometry data used throughout the study of a, ILCs, b, lymphocytes and c, DCs, myeloid cells and eosinophils.
Extended Data Fig. 3 Effects of oxaliplatin and carboplatin on the immune infiltrate of the TC-1 tumor.
Therapeutic responses of WT and nude mice bearing a TC-1 tumor treated with a, Cisplatin (CDDP) n = 8, b, Carboplatin (Cb) n = 6 or c, Oxaliplatin (Ox) n = 6, reflected by tumor growth kinetics. Results are shown as mean ± SEM. d–l Flow cytometry analysis of immune cells infiltrating the tumor one and seven days after an Ox or Cb treatment. Numbers are shown for 300 000 total viable cells from each tumor. n = 5. Numbers of d, ILC1s, e, ILC2s, f, CD45+ cells, g, CD8+ cells, h, CD4+ cells, i, B cells, j, CD11c+ cells, k, CD11b+ cells, l, MDSCs. Results are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using two-way anova and Tukey’s multiple comparison test (a–l).
Extended Data Fig. 4 Effects of paclitaxel, doxorubicin and 5-fluorouracil on the immune infiltrate of the TC-1 tumor.
a–g, Flow cytometry analysis of immune cells infiltrating the tumor seven days after a Paclitaxel (Paclitxl), a Doxorubicine (Doxo) or a 5FU treatment. Numbers are shown for 300 000 total viable cells from each TC-1 tumor. n = 5. Numbers of a, ILC3s one and seven days after treatment, b, CD45+ cells, c, CD4+ and CD8+ cells, d, B cells, e, CD11c+ cells, f, CD11b+ cells, g, MDSCs. h, Therapeutic responses of WT mice bearing a 4T1 tumor treated with CDDP at day 10, reflected by tumor growth kinetics. n = 7. Tumor growth results are shown as mean ± SEM. i–o Flow cytometry analysis of immune cells infiltrating the tumor one and seven days after CDDP. Numbers are shown for 300 000 total viable cells from each 4T1 tumors. n = 5. Numbers of i, CD45+ cells, j, CCR6+ ILC3s, k, CD4+ and CD8+ cells, l, B cells, m, CD11c+ cells, n, CD11b+ cells, o, MDSCs. Results are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using two-way anova and Tukey’s multiple comparison test (a, c, g, i–o), one-way anova (b, d–f) or using two tailed multiple unpaired T Test (h).
Extended Data Fig. 5 Importance of RORγt+ cells in the anti-tumor immune response.
Flow cytometry analysis of a, RORγt+IL-17+ Th17 and b, CCR6+ and NKP46+ IL-17+ ILC3s cells from WT mice intestine treated with PBS, GSK805 or Digoxin n = 5 and of c, RORγt+ Th17 and d, CCR6+ ILC3 from TC-1 tumor seven days after CDDP treated with Digoxin or GSK805, n = 7. Numbers for 300 000 CD45+ cells. e-p Flow cytometry analysis of immune cells infiltrating TC-1 tumors one, three and seven days after a CDDP and or Digoxin treatment. Numbers are shown for 300 000 total viable cells from each TC-1 tumor. n = 7. Numbers of e, ILC3s, f, ILC2s, g, ILC1s, h, NKs, i, CD8 + cells, j, CD4 + cells, k, B cells, l, DCs, m, macrophages, n, M-MDSCs, o, PMN-MDSCs and p, eosinophils. Results are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using one-way anova (a–d) and two-way anova and Tukey’s multiple comparison test (e–o).
Extended Data Fig. 6 Importance of ILC3s in the antitumor immune response.
a, Therapeutic response of WT mice bearing urethane induced lung carcinoma to CDDP, Digoxin and GSK805 fourteen days after the CDDP treatment, reflected by the number of tumor foci, n = 10. b, Therapeutic response of BALB/c WT mice bearing 4T1 tumors to CDDP alone or in combination with Digoxin as reflected by tumor growth kinetics. n = 5. c, Flow cytometry analysis of the numbers of NK and ILCs from TC-1 tumors. Numbers are shown for 300 000 total viable cells from each TC-1 tumor, n = 5. d–g, Flow cytometry analysis of immune populations in the spleen of Rorcfl/flCd4cre and littermate control mice, n = 5. Percentages of d, CCR6+ ILC3s in ILCs and of e, Th17 in CD4+ cells from the spleen. f, flow cytometry analysis of the numbers of CCR6+ ILC3 in TC-1 tumors of Rorcfl/flCd4cre mice or littermate control mice. n = 5 g, Percentage of Th17 cells found in the spleen of Rorcfl/flCd4cre mice seven days after an adoptive transfer of Th17, identified by their cytotracker expression. n = 5. h, Therapeutic response of littermate controls Rorcfl/flCd4+/+ mice bearing TC-1 tumors to CDDP alone or in combination with Digoxin as in Fig. 2d, as reflected by tumor growth kinetics. n = 6. Flow cytometry expression of checkpoint inhibitors on i, CD4+ cells and j, CD8+ cells from TC-1 tumors on WT mice seven days after a CDDP treatment. n = 5. k, Therapeutic response of littermate controls Rorcfl/flCd4+/+ mice bearing TC-1 tumors to CDDP in combination with anti-CTLA-4 and Digoxin as in Fig.3b, reflected by tumor growth. n = 5. l, Therapeutic response of WT mice bearing a TC-1 tumor treated with anti-CTLA-4 as in Fig. 3a, reflected by tumor growth. n = 7. m, Therapeutic response of littermate controls Rorcfl/flCd4+/+ mice bearing MC38 tumors to ICB in combination with Digoxin as in Fig. 3g, reflected by tumor growth. n = 5. All tumor growth results are shown as mean ± SEM and experiments followed the experimental setting depicted above each data or referred to the main figures; other data are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using two-way anova and Tukey’s multiple comparison test (b, c, f, h–m), two tailed unpaired T-test (d, e), and one-way anova (a).
Extended Data Fig. 7 Impact of CDDP on CXCL10 production by intratumor immune cells.
Violin plot showing expression level of a, Lta and b, Ltb genes in cells belonging to the ILC3 CCR6 cluster at each time point, measured by sc RNA-seq from TC-1 tumors, as described in Fig. 1. c–m, Flow cytometry analysis of CXCL10 expressing cells from TC-1 tumors treated with PBS or CDDP, one, three and seven days before. Percentages of CXCL10+ in c, ILC1s, d, ILC2s, e, NKs, f, CD4+ cells, g, CD8+ cells, h, DCs, i, B cells, j, macrophages, k, M-MDSCs, l, PMN-MDSCs, m, eosinophils, n = 6. n, numbers of eosinophils from tumors treated as in c-m n = 6. Numbers are shown for 300 000 total viable cells from each TC-1 tumor. o, representative flow cytometry plot of CXCL10 expression. Results are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using two-way anova and Tukey’s multiple comparison test (c–n).
Extended Data Fig. 8 Impact of CXCR3 on CDDP driven intratumor immune recruitment.
a–g Flow cytometry analysis of immune populations in TC-1 tumors treated with anti-CXCR3 and CDDP and analyzed seven days after CDDP. Numbers are shown for 300 000 total viable cells from each TC-1 tumor. n = 5. Numbers of a, CCR6+ ILC3s, b, CD45+ cells, c, CD8+ and CD4+ cells, d, B cells, e, CD11c+ cells, f, CD11b+ cells and g, MDSCs. h, representative flow cytometry plot of KI67, IL-2, Granzyme B, IFNγ and TNFα expression. Results are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using one-way anova (a, b, d–f) and two-ways anova plus Tukey’s multiple comparison test (c, g).
Extended Data Fig. 9 CCL20 is an important chemokine in CDDP triggered intratumor immune response.
KI67 expression on CCR6+ ILC3s from TC-1 tumors one or seven days after CDDP by a, flow cytometry. n = 5. and by b, sc RNA-seq. c, Fold increase of cytokine expressions relative to PBS in TC-1 tumors treated with CDDP using 14 cytokine bioplex. n = 5. d, Flow cytometry analysis of the percentage of cells from TC-1 tumors expressing CCL20 two days after a CDDP treatment. n = 5. e CCL20 production in vitro by TC-1 cells treated with various chemotherapies at their IC50 for two days. n = 3. f–j Flow cytometry analysis seven days after CDDP of immune cells infiltrating TC-1 tumors treated with α-CCL20 antibody. Numbers are shown for 300 000 total viable cells from each TC-1 tumor. n = 5. Numbers of f, CD45+ cells. g, B cells. h, CD11c+ cells. i, CD11b+ cells and j, MDSCs. k, Flow cytometry analysis of CCL20 expression by TC-1 cells transfected with a control Sh RNA (Sh C-) or directed against CCL20 (Sh CCL20) and treated in vitro with PBS or CDDP. n = 6. l, Therapeutic response of TC-1 Sh C- and TC-1 Sh CCL20 to CDDP as reflected by tumor growth kinetics. n = 17. m, representative flow cytometry plot of CCL20 expression in TC-1, MC38 and DCs, n, Flow cytometry analysis of the percentage of cells from MC38 tumors expressing CCL20 two days after an ICB treatment. EC: endothelial cells, MSC: mesenchymal stromal cells MC: myeloid cells DC: dendritic cells TC: tumor cells n = 5. All tumor growth results are shown as mean ± SEM and experiments followed the experimental setting depicted above each data or referred to the main figures and are representative of three independent experiments; other data are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using one-way anova (e–i), two-way anova and Tukey’s multiple comparison test (a–d, j–n).
Extended Data Fig. 10 IL-1β is a key factor for antitumor immune responses.
a, Flow cytometry analysis of Caspase-1 cleavage in myeloid cells MSC-2 treated in vitro with LPS and CDDP or LPS and Nigericin as a positive control for 24 h. n = 6. b, IL-1β production by myeloid cells MSC-2 treated in vitro with LPS and CDDP or LPS and Nigericin as a positive control for 24 h. n = 4. c-g, In vivo Flow cytometry analysis of Pro-IL-1β expression in immune cells from TC-1 tumors seven day after a CDDP or a PBS treatment Results show the numbers of cells from 300 000 total viable cells from each tumor. n = 5. Numbers of c, eosinophils, d, macrophages, e, M-MDSCs, f, PMN-MDSCs, g, DCs. h, Representative flow cytometry plot of CD69 expression in ILC3s. i, Therapeutic response of WT and TCRδ-/- mice bearing TC-1 tumors treated with CDDP or PBS reflected by tumor growth following the experimental setting depicted above. Flow cytometry analysis of the numbers of j, CD4+ and CD8+ cells of MC38 tumors from WT mice treated with ICB and IL-1RA as in Fig. 6l. n = 5. Numbers are shown for 300 000 total viable cells from each MC38 tumor. Therapeutic response of k, littermate controls Rorcfl/flCd4+/+ mice, n = 5, and l, Rorc–/– mice, n = 5, bearing MC38 tumors to ICB in combination with IL-1RA reflected by tumor growth following the experimental setting depicted above each data. m, Therapeutic response of WT mice bearing a MC38 tumor treated with rIL-1β and rCCL20 alone or in combination with ICB, reflected by tumor growth following the experimental setting depicted above, n = 5. All tumor growth results are shown as mean ± SEM and experiments followed the experimental setting depicted above each data or referred to the main figures and are representative of three independent experiments.; other data are shown as mean ± SD and are representative of three independent experiments. Statistical significance was determined using one-way anova (a, b), two-way anova and Tukey’s multiple comparison test (c–g, i–m).
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Bruchard, M., Geindreau, M., Perrichet, A. et al. Recruitment and activation of type 3 innate lymphoid cells promote antitumor immune responses. Nat Immunol 23, 262–274 (2022). https://doi.org/10.1038/s41590-021-01120-y
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DOI: https://doi.org/10.1038/s41590-021-01120-y
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