Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade – Nature.com

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Nature Cancer volume 1, pages 75–85 (2020)Cite this article
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Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/T_reg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1–programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.
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Source data for Figs. 1–7 and Extended Data Figs. 1–7 are provided with the paper. All other data supporting the findings of this study are available from the corresponding author on reasonable request.
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We thank C. Zandueta and O. Rogero for technical assistance, and J. M. Kurie (The University of Texas MD Anderson Cancer Center, Houston, TX) for gifting the 393P cells. This study was supported by the Foundation for Applied Medical Research (FIMA), CIBERONC (CB16/12/00443 and CB16/12/00364), Fundación Científica de la Asociación Española Contra el Cáncer, Fundación Ramón Areces, Juan Serrano, Instituto de Salud Carlos III–Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional ‘Una manera de hacer Europa’ (FEDER; PI17/00411, PI16/01352, PI16/01821 and AC14/00034), La Caixa Foundation, Caja Navarra Foundation and the Spanish Ministry of Economy and Competitiveness (SAF2015-71606R, SAF2016-78568-R and RTI 2018-094507-B-100). F.E. is funded by a predoctoral fellowship from the Asociación de Amigos de la Universidad de Navarra and from La Caixa Foundation. S.O.-E. was funded by a predoctoral fellowship from the Asociación de Amigos de la Universidad de Navarra and is now supported by an FPU fellowship. M.F.S. is supported by a Miguel Servet type I contract from Instituto de Salud Carlos III–Fondo de Investigación Sanitaria.
Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Daniel Ajona, Sergio Ortiz-Espinosa, Francisco Exposito, Alfonso Calvo, Karmele Valencia, Miriam Redrado, Ana Remírez, Fernando Lecanda, Irati Macaya, Yaiza Senent, Cristina Bértolo, Cristina Sainz, Ignacio Gil-Bazo, Silvestre Vicent, Luis M. Montuenga & Ruben Pio
Navarra Institute for Health Research (IdISNA), Pamplona, Spain
Daniel Ajona, Teresa Lozano, Francisco Exposito, Alfonso Calvo, Karmele Valencia, Miriam Redrado, Fernando Lecanda, Diego Alignani, Juan J. Lasarte, Irati Macaya, Cristina Bértolo, Cristina Sainz, Ignacio Gil-Bazo, Jose M. Lopez-Picazo, Alvaro Gonzalez, Jose L. Perez-Gracia, Carlos E. de Andrea, Silvestre Vicent, Miguel F. Sanmamed, Luis M. Montuenga & Ruben Pio
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
Daniel Ajona, Francisco Exposito, Alfonso Calvo, Karmele Valencia, Fernando Lecanda, Diego Alignani, Cristina Bértolo, Cristina Sainz, Ignacio Gil-Bazo, Jose M. Lopez-Picazo, Jose L. Perez-Gracia, Carlos E. de Andrea, Silvestre Vicent, Miguel F. Sanmamed, Luis M. Montuenga & Ruben Pio
Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
Daniel Ajona, Sergio Ortiz-Espinosa, Karmele Valencia, Alvaro Gonzalez & Ruben Pio
Program in Immunology and Immunotherapy, CIMA, University of Navarra, Pamplona, Spain
Teresa Lozano, Juan J. Lasarte & Miguel F. Sanmamed
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
Francisco Exposito, Alfonso Calvo, Fernando Lecanda, Carlos E. de Andrea & Luis M. Montuenga
Cytometry Platform, CIMA, University of Navarra, Pamplona, Spain
Diego Alignani
Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
Ignacio Gil-Bazo, Iñaki Eguren-Santamaría, Jose M. Lopez-Picazo, Jose L. Perez-Gracia & Miguel F. Sanmamed
Clinical Chemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
Alvaro Gonzalez
Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
Carlos E. de Andrea
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D.Ajona and R.P. supervised the study and were responsible for the study conception and design. J.M.L.-P., M.F.S., A.G., J.L.P.-G., I.G.-B., I.E.-S. and C.E.A. provided clinical samples. D.Ajona, S.O.-E., F.E., K.V., Y.S., S.V., C.S. and F.L. performed the in vivo studies. K.V. and C.B. prepared the viral vectors and the stable clones. D.Ajona, A.C. and M.R. were responsible of the Luminex analysis. D.Ajona and A.R. carried out the immunohistochemistry experiments. T.L. and J.J.L. performed the ELISpot assay. D.Alignani optimized and supervised the flow cytometry experiments. D.Ajona, I.M. C.B., A.R. and S.V. carried out the mRNA and protein expression analyses. D.Ajona, R.P., T.L., J.J.L., F.L., A.C., M.R., I.E.-S., M.F.S., C.E.A. and L.M.M. were responsible for the analysis and interpretation of the data. D.Ajona, M.F.S., I.E.-S. and R.P. performed the statistical analysis. D.Ajona and R.P. wrote the manuscript. All authors critically reviewed the manuscript and approved its final version.
Correspondence to Daniel Ajona.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Individual follow-up of 393P tumor volumes in mice treated with anti-PD-1 (n=10 mice), STS (n=10 mice), the combination of both (n=8 mice) or vehicle (Control; n=11 mice). b, Individual follow-up of LLC tumor volumes in mice treated with anti-PD-1 (n=8 mice), STS (n=6 mice), the combination of both (n=6 mice) or vehicle (Control; n=8 mice). Numerical source data are provided as a source data file.
Source data
a, Flow cytometric analysis of the proportion of intratumoral CD4, NK (NK1.1) and B (CD19) cells at day 18 after subcutaneous inoculation of LLC cells (Control, n=8 tumors; anti-PD-1, n=8 tumors; STS, n=5 tumors; STS/anti-PD-1, n=7 tumors). b, Expression of PD-1 in tumor-infiltrating CD4 T cells of the experiment shown in section a. Data are expressed as the mean fluorescence intensity (MFI) ± s.e.m. c, Flow cytometric analysis of the proportion of intratumoral total MDSCs, monocytic MDSCs (M-MDSCs; CD11b/Ly6C⁺/Ly6G^low), granulocytic MDSCs (G-MDSC; CD11b/Ly6C⁺/Ly6G⁺), macrophages (F4/80) and DCs (CD11c). The number of tumors per group was: Control, n=7 tumors; anti-PD-1, n=8 tumors; STS, n=5 tumors; STS/anti-PD-1 combination, n=7 tumors. Data are expressed as the mean of the percentage of total leukocytes (CD45) ± s.e.m. In all cases, the statistical significance of the differences were evaluated using the two-sided Kruskal-Wallis test with the Mann-Whitney U-test as the post hoc test. Numerical source data are provided as a source data file.
Source data
Flow cytometric analysis of the proportion of peripheral blood CD8, CD4, T_reg cells, NK (NK1.1) and B (CD19) cells in mice after inoculation of LLC cells and two cycles of 48 hours of STS (day 12 after tumor implantation) (Control, n=6 mice; anti-PD-1, n=6 mice; STS, n=5 mice; STS/anti-PD-1, n=6 mice). Data are expressed as the percentage of total lymphocytes except for T_reg cells, which are expressed as the percentage of total CD4 T cells (means ± s.e.m.). The differences between experimental groups were analyzed using the two-sided Kruskal-Wallis test with the Mann-Whitney U-test as the post hoc test. Numerical source data are provided as a source data file.
Source data
a, Cropping images from the western blot analysis of LC3-I and LC3-II in LLC cells cultured under normal or STS-like conditions for 48 hours. This experiment was performed twice with similar results. b, Cropping images from the western blot analysis of LC3-I and LC3-II in LLC cells cultured under normal or STS-like conditions in the presence of 1 µg ml^–1 of rIGF-1 or vehicle for 48 and 72 hours. This experiment was performed once. Unprocessed images of blots are provided as source data file.
Source data
Individual follow-up of 393P tumor volumes in mice treated with PQ401 (n=10 mice), anti-PD-1 (n=11 mice), or the combination of both (n=10 mice) or vehicle (Control; n=11 mice). Numerical source data are provided as a source data file.
Source data
a, Flow cytometric analysis of the proportion of intratumoral total MDSCs, monocytic MDSCs (M-MDSCs; CD11b/Ly6C⁺/Ly6G^low), granulocytic MDSCs (G-MDSC; CD11b/Ly6C⁺/Ly6G⁺), macrophages (F4/80), DCs (CD11c), CD4 T, NK (NK1.1) and B (CD19) cells at day 19 after inoculation of LLC cells (n=8 tumors per group except for anti-PD-1 group in CD4 T, NK and B cells analyses; n=7). Data are expressed as the percentage of total leukocytes (CD45). b, Expression of the markers PD-1, GITR, and LAG-3 in tumor-infiltrating CD4 T cells. The number of tumors per group was: Control, n=8 tumors; anti-PD-1, n=7 tumors; PQ401, n=8 tumors; PQ401/anti-PD-1 combination, n=8 tumors. Data are expressed as the mean of fluorescence intensity (MFI) ± s.e.m. The differences between experimental groups were analyzed using the two-sided Kruskal-Wallis test with the Mann-Whitney U-test as the post hoc test. Numerical source data are provided as a source data file.
Source data
Flow cytometric analysis of the proportion of splenic CD8, CD4, B cells (CD19), NK (NK1.1) and T_reg cells, MDSCs (total MDSCs, M-MDSCs, and G-MDSCs), macrophages, and DCs in tumor-bearing mice at day 19 after inoculation of LLC cells (n=8 mice per group). Data are expressed as the percentage of total leukocytes (CD45), except for T_reg cells, which are expressed as the percentage of total CD4 T cells (means ± s.e.m.). The differences between experimental groups were analyzed using the two-sided Kruskal-Wallis test with the Mann-Whitney U-test as the post hoc test. No statistically significant differences were found. Numerical source data are provided as a source data file.
Source data
Supplementary Tables 1 and 2 and Supplementary Figs. 1 and 2.
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Unprocessed Western blots
Numerical source data
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Numerical source data
Unprocessed Western blots
Numerical source data
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Ajona, D., Ortiz-Espinosa, S., Lozano, T. et al. Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nat Cancer 1, 75–85 (2020). https://doi.org/10.1038/s43018-019-0007-9
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Received: 30 August 2019
Accepted: 14 November 2019
Published: 13 January 2020
Issue Date: January 2020
DOI: https://doi.org/10.1038/s43018-019-0007-9
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