Abstract
Anti-programmed death-1 (PD-1) immunotherapy that aims to restore T cell activity in cancer patients frequently leads to immune-related adverse events such as colitis. However, the underlying mechanism is still elusive. Here, we find that Pdcd1-deficient mice exhibit disrupted gut microbiota and aggravated dextran sulfate sodium (DSS)-induced colitis. In addition to T cells, PD-1 is also substantially expressed in colonic lymphoid tissue inducer (LTi) cells. During DSS-induced colitis, LTi cell activation is accompanied by increased PD-1 expression, whereas PD-1 deficiency results in reduced interleukin-22 (IL-22) production by LTi cells and exacerbated inflammation. Mechanistically, activated LTi cells reprogram their metabolism toward carbohydrate metabolism and fatty acid synthesis, while fatty acid oxidation (FAO) is unchanged. However, PD-1 deficiency leads to significantly elevated FAO in LTi cells, which in turn attenuates their activation and IL-22 production. Consistently, FAO suppression efficiently restores IL-22 production in Pdcd1−/− LTi cells. Thus, our study provides unforeseen mechanistic insight into colitis occurrence during anti-PD-1 immunotherapy through LTi cell metabolic reconfiguration.
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Data availability
RNA-seq and scRNA-seq data generated in this study are publicly available in the NCBI Gene Expression Omnibus repository under the accession number GSE144687. This study did not generate any unique codes. All other data can be made available from the authors on reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank Fuping You of Peking University (Beijing, China) for technique help. We thank Xiaohuan Guo of Tsinghua University (Beijing, China) for providing the C. rodentium strain and for assistance with the mixed bone marrow chimera experiments. We thank Huan Wang of Peking University for assistance with Seahorse assays. We thank all of the staff of the animal department for their help. This work is supported by the National Natural Science Foundation of China (no. 31770957, no. 91842102 and no. 32170896), and the Natural Science Foundation of Beijing (no. 18G10645).
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C.Z. conceived the project. D.W. performed all of the experiments. L.H. and Yime Zhang. helped with bioinformatic analyses. M.H. performed the scRNA-seq. Y.D. helped with cell sorting. G.R., X.Z., Z.L. P.L., Yinlian Zhang, S.C., J.L., Y.S. and P.W. helped in some experiments and data analysis. J.X. generated the critical mice tool. C.Z. and D.W. wrote the manuscript. C.Z. supervised the project.
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Extended data
Extended Data Fig. 1 PD-1 deficiency results in disturbed microbiota and aggravated colitis.
a, Differences in fecal taxa in Pdcd1+/+ and Pdcd1-/- mice were shown in taxonomic cladogram from linear discriminant analysis of effect size (LEfSe) (green, most abundant in Pdcd1+/+ mice; red, most abundant in Pdcd1-/- mice). b, Proportions of IgA-coating fecal bacteria from Pdcd1-/- mice and Pdcd1+/- littermates were examined by flow cytometry (n = 5 per group; *p = 0.0467). c, gut barrier integrity in Pdcd1+/+ and Pdcd1-/- mice were assessed by FITC-dextran 4 (FD4, molecular mass, 4 kDa) gavage at 10ml/kg. FD4 in mice serum was examined after 4 hours by fluorescence intensity (n = 5 per group; ns). d, Colitis was induced in Pdcd1-/- mice and Pdcd1+/- littermates by 3% DSS. Body weight change was examined every day (n = 5 per group; *p = 0.0484). e, On day 7 of DSS-induced colitis, mice were sacrificed and colon length was measured (n = 5 per group; **p = 0.0029). Data are representative of two independent experiment (a) or at least three independent experiments (b-e). Data are presented as the mean ± s.d., and statistical significance was determined by two-sided unpaired t-test (b, c, e) and two-sided paired t-test (d). Ns, not significant, *p < 0.05, **p < 0.01.
Extended Data Fig. 2 PD-1 expression on colonic LTi is upregulated during activation.
a, PD-1 expression on colonic ILCs, γδT, NKT, monocytes, and DC was examined by flow cytometry. Percentages of PD-1+ cells and their PD-1 MFI were calculated (n = 4 per group; ns, ns, ***p < 0.0001, ***p < 0.0001; ***p = 0.0008, ***p < 0.0001, ***p < 0.0001, ***p < 0.0001). b, Gating strategy for ILC subsets, including LTi, T-bet-(CCR6-) ILC3, T-bet+(NKp46-) ILC3, NKp46+ ILC3, ILC1/cNK, and ILC2. c, On day 7 of DSS-induced colitis, proportion of IL-22-producing lymphocytes in colon was analyzed (mean ± s.d.; n = 6). d, PD-1 expression between colonic LTi of B6 (Rag2+/+) and Rag2-/- mice were compared. Proportion of PD-1+ LTi and their PD-1 MFI were calculated (n = 5 per group; ***p < 0.0001, **p = 0.0027). e, IL-22 production by colonic LTi of mice in steady state and DSS-induced colitis (on day 7) was examined. Proportion of IL-22+ LTi and their IL-22 MFI were compared (n = 4 per group; **p = 0.0028, *p = 0.0189). f, On day 7 of DSS-induced colitis, forward and side scatters (FSC-A and SSC-A) of PD-1high and PD-1- colonic LTi were examined. Mean values of FSC-A and SSC-A were compared (n = 4 per group; ***p = 0.0001, ***p < 0.0001). g, On day 7 of DSS-induced colitis, IL-17A expression in PD-1high and PD-1- colonic LTi was examined. Proportion, IL-17A MFI and number of IL-17A+ LTi were compared (n = 5 per group; ***p = 0.0008, *p = 0.0454, **p = 0.0015). h, PD-1 expression on in vitro cultured LTi treated with heat-killed bacteria or PBS (left), or bacterial culture supernatant or culture medium (right) was examined. i, 7 days post C. rodentium infection, PD-1 expression on colonic LTi was examined. Proportion of PD-1+ LTi and their PD-1 MFI were calculated (n = 4 per group; ns, ns). Data are representative of at least three independent experiments. Data are presented as the mean ± s.d., and statistical significance was determined by two-sided unpaired t-test (a, d-g, i). Ns, not significant, *p < 0.05, **p < 0.01, ***p < 0.001.
Extended Data Fig. 3 Impact of PD-1 deficiency on colonic LTi activation.
a, Percentage and number of colonic LTi in Pdcd1+/+ and Pdcd1-/- mice were calculated (n = 4 per group; ns, ns). b, On day 7 of DSS-induced colitis, proportion, IL-22 MFI and number of IL-22+ colonic LTi in Pdcd1-/- and Pdcd1+/- (littermate) mice were analyzed (n = 5 per group; ***p = 0.0006, *p = 0.0489, *p = 0.0425). c, On day 3 of DSS-induced colitis, proportion, IL-17A MFI and number of IL-17A+ colonic LTi in Pdcd1+/+Rag2-/- and Pdcd1-/-Rag2-/- mice were analyzed (n = 5 per group; ns, ns, ns). (d-h) Pdcd1+/+Rag2-/- and Pdcd1-/-Rag2-/- mice were subjected to C. rodentium infection. d, Body weight was measured daily (n = 5 per group; ***p < 0.0001). Colon length (e) (n = 5 per group; *p = 0.0436) and H&E staining indicated tissue damage (f) was assessed on day 3, g, The bacteria burdens in feces, spleen, and liver were assessed on day 3 and 7 (n = 5 per group; *p = 0.0235, *p = 0.0389; *p = 0.0242, *p = 0.0142; *p = 0.0104, *p = 0.0492). CFU, colony-forming unit. h, On day 3, proportion, IL-22 MFI and number of IL-22+ colonic LTi were analyzed (n = 5 per group; *p = 0.0182, **p = 0.0029, *p = 0.0331). i, Under different stimulations, proportion and IL-22 MFI of IL-22+ siLP LTi in Pdcd1+/+Rag2-/- and Pdcd1-/-Rag2-/- mice were examined (n = 4 per group; ***p < 0.0001, ***p < 0.0001, ***p < 0.0001; *p = 0.0267, *p = 0.0423, ***p = 0.0001). P/I, PMA+ionomycin. j, Construction strategy for Pdcd1h/h mice. k, On day 7 of DSS-induced colitis, proportion and hPD-1 MFI of hPD-1+ colonic LTi in Pdcd1h/+ and Pdcd1h/- mice were assessed (n = 4 per group; ns, ns). l, PD-1 expression on lineage-RORγt+ siLP lymphocytes of Pdcd1fl/-Rorc-Cre and Pdcd1fl/- (littermate) mice were compared. Data are representative of at least three independent experiments. Data are presented as the mean ± s.d., and statistical significance was determined by two-sided unpaired t-test (a-c, e, g-i, k) and two-sided paired t-test (d). Ns, not significant, *p < 0.05, **p < 0.01, ***p < 0.001.
Extended Data Fig. 4 PD-1 signaling represses STAT3 phosphorylation in activated LTi.
a, Sorted LTi were stimulated with IL-23 (0.5 ng/ml) for 25 min, in presence or absence of rPD-L1 (5 µg/ml). Afterwards, STAT3 phosphorylation was examined by flow cytometry. b, On day 7 of DSS-induced colitis, colonic lymphocytes were collected from Pdcd1+/+ and Pdcd1-/- mice. STAT3 phosphorylation (pSTAT3) in LTi was compared by flow cytometry. Isotype antibody staining was used as negative control. MFI of pSTAT3 was calculated (n = 5 per group; ns). Data are representative of at least three independent experiments. Data are presented as the mean ± s.d., and statistical significance was determined by two-sided unpaired t-test (b). Ns, not significant.
Extended Data Fig. 5 scRNA-seq reveals metabolic reprogramming during ILC3 activation.
a, Lineage- CD127+ siLP ILCs sorted from B6 mice were subjected to single-cell RNA-sequencing. The cells were clustered into three subsets, ILC1, ILC2, and ILC3 (left), based on their Rorc, Gata3, and Ncr1 expression (right). b, Scorings of LTi (top) and Nkp46+ ILC3 (bottom) based on the ILC3 activation module was correlated with their Il22 expression in scatter plot. Pearson correlation was used to indicate the strength of linear relationship (95% confidence intervals by default). c, Differentially expressed genes in inactivated NKp46+ ILC3 and activated NKp46+ ILC3 clusters were shown with heatmap. d, Signature metabolic genes in inactivated NKp46+ ILC3 and activated NKp46+ ILC3 clusters were shown in violin plot. e, Enrichment of classical metabolic pathways (including carbohydrate metabolism, lipid metabolism, and respiration) in inactivated NKp46+ ILC3 and activated NKp46+ ILC3 was shown in radar chart. f, Respective enrichment of carbohydrate metabolism, lipid metabolism, and respiration pathways in inactivated NKp46+ ILC3 and activated NKp46+ ILC3, using the differentially expressed genes in (c), was compared in density plots. g, Enrichment of fatty acid oxidation and lipid biosynthesis in inactivated NKp46+ ILC3 and activated NKp46+ ILC3, using the differentially expressed genes in (c), was compared with density plot. ND, not detected, in the differentially expressed genes in (c).
Extended Data Fig. 6 Excessive FAO suppresses ILC3 activation.
a, Representative Seahorse palmitate-FAO assay result showed the impact of palmitate (PA) on FAO of LTi (n = 5 per group). b, Basal OCR, ATP-linked OCR, maximal OCR and SRC were quantified (n = 3 per group; **p = 0.0097, **p = 0.0082, *p = 0.0163, *p = 0.0462). c, After a 3-day PA (20 μM) or vehicle treatment, IL-22 expression in activated LTi was assessed . Proportion of IL-22+ LTi and their IL-22 MFI were calculated (n = 4 per group; **p = 0.001, *p = 0.0117). d, Viability of LTi after PA (100 μM) treatment was assessed (n = 5 per group; ns). e, CPT1A overexpression in LTi was measured by qRT-PCR (n = 5 per group; *p = 0.0297). f, Impact of CPT1A on IL-22 production in LTi were assessed. Proportion of IL-22+ LTi and their IL-22 MFI were calculated (n = 5 per group; *p = 0.0436, ***p < 0.0001). g, After a 3-day PA or vehicle treatment, IL-22 production in activated NKp46+ ILC3 was assessed. Proportion of IL-22+ NKp46+ ILC3 and their IL-22 MFI were calculated (n = 5 per group; ***p < 0.0001, ***p < 0.0001). (h and i) Rag2-/- mice were fed with HFD (high fat diet) or CD (chow diet) for 5 weeks. IL-22 expression in siLP NKp46+ ILC3 (h) and colonic LTi (i) was examined. Proportion of IL-22+ siLP NKp46+ ILC3 and their IL-22 MFI (n = 4 per group; *p = 0.0269, *p = 0.0151)(h), and proportion, IL-22 MFI and number of IL-22+ colonic LTi (n = 4 per group; *p = 0.0298, *p = 0.0477, *p = 0.0496)(i), were calculated. (j and k) Enriched features in PA untreated (j) and treated (k) LTi was analyzed using two-sided GSEA adopted permutation-test. Nominal p-value and NES were calculated. Data are representative of at least three independent experiments (a-i) or two independent experiments (j-k). Data are presented as the mean ± s.d., and statistical significance was determined by two-sided unpaired t-test (b-i). Ns, not significant, *p < 0.05, **p < 0.01, ***p < 0.001.
Extended Data Fig. 7 FAO inhibition restores IL-22 production in PD-1 deficient LTi.
a, Expression of CPT1A in colonic LTi from wild-type (Pdcd1+/+) and Pdcd1-/- mice in steady state was examined by flow cytometry. MFI of CPT1A was calculated (n = 4 per group; ns). b, FAO inhibitor Oxfenicine or vehicle (H2O) was added to siLP LTi sorted from Pdcd1+/+Rag2-/- and Pdcd1-/-Rag2-/- mice. After 4 days, the cells were harvested and stimulated by IL-23 (0.5 ng/ml) for 3 hours. Afterwards, IL-22 secretion was assessed by intracellular cytokine staining. c, Proportion and IL-22 MFI of IL-22+ LTi in (b) were calculated (n = 4 per group; **p = 0.0033, ns; **p = 0.0058, ns). d, Wild-type and Pdcd1-/- mice were injected (i.p.) with Oxfenicine or H2O during DSS-induced colitis. On day 7, mice were sacrificed, and IL-22 production in colonic LTi was examined by intracellular cytokine staining. Proportion, IL-22 MFI and cell number of IL-22+ LTi were calculated (n = 4 per group; **p = 0.0044, *p = 0.0119; **p = 0.0095, ***p = 0.0005; **p = 0.0033, ns). e, Cpt1a knockdown in LTi cells was assessed by qRT-PCR (n = 5 per group; ***p = 0.0009). f, IL-22 production by shScram (scramble) or shCpt1a lentivirus infected LTi was assessed by intracellular cytokine staining. Proportion and IL-22 MFI of IL-22+ LTi were calculated (n = 5 per group; **p = 0.0027, *p = 0.0213). Data are representative of at least three independent experiments. Data are presented as the mean ± s.d., and statistical significance was determined by two-sided unpaired t-test (a, c-f). Ns, not significant, *p < 0.05, **p < 0.01, ***p < 0.001.
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Wu, D., Hu, L., Han, M. et al. PD-1 signaling facilitates activation of lymphoid tissue inducer cells by restraining fatty acid oxidation. Nat Metab 4, 867–882 (2022). https://doi.org/10.1038/s42255-022-00595-9
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DOI: https://doi.org/10.1038/s42255-022-00595-9