Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+CH25H+IL-21+PD-1+CD4+ T helper cells (“CXCL13+ TH”) and Granzyme K+ PD-1+ effector-like CD8+ T cells, whereas terminally exhausted CD39hiTOXhiPD-1hiCD8+ T cells dominated in nonresponders. CD4+ and CD8+ T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1+TCF-1+ (Progenitor-exhausted) CD8+ T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8+ T cell differentiation occurs upon ICB. We found that these Progenitor CD8+ T cells interact with CXCL13+ TH within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ TH control the differentiation of tumor-specific Progenitor exhasuted CD8+ T cells following ICB.
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This study was funded by Regeneron Inc. We thank members of the Merad and Brown laboratories at the Marc and Jennifer Lipschultz Precision Immunology Institute at Mount Sinai and the Tisch Cancer Institute for insightful discussions and feedback; and the Mount Sinai Flow Cytometry Core, the Human Immune Monitoring Center and Biorepository and Pathology CoRE Laboratory of the Icahn School of Medicine at Mount Sinai for support. We thank the patients and their families for participating in the clinical trials. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. S.G. was partially supported by National Institutes of Health (NIH) grants CA224319, DK124165, CA263705 and CA196521. A.O.K. and T.U.M. were supported in part by the Tisch Cancer Institute Cancer Center Support Grant (P30 CA196521). A.O.K. and E.H. were supported in part by R01 AI153363. M.M. was partially supported by NIH grants CA257195, CA254104 and CA154947.
M.M. serves on the scientific advisory board and holds stock from Compugen Inc., Myeloid Therapeutics Inc., Morphic Therapeutic Inc., Asher Bio Inc., Dren Bio Inc., Nirogy Inc., Oncoresponse Inc., Owkin Inc., DEMBIO and Larkspur Inc. M.M. serves on the scientific advisory board of Innate Pharma Inc., DBV Inc., Pionyr Inc., OSE Inc. and Genenta Inc. M.M. receives funding for contracted research from Regeneron Inc. and Boerhinger Ingelheim Inc. S.G. reports past consultancy or advisory roles for Merck and OncoMed; research funding from Regeneron Pharmaceuticals related to the current study, and research funding from Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, EMD Serono, Pfizer and Takeda, unrelated to the current work. S.G. is a named coinventor on an issued patent (US20190120845A1) for multiplex immunohistochemistry to characterize tumors and treatment responses. The technology is filed through Icahn School of Medicine at Mount Sinai (ISMMS) and is currently unlicensed. This technology was used to evaluate tissue in this study and the results could impact the value of this technology. N. Fiaschi, B.K., M.D., L.L., C.A., M.N., Y.W., W.W., N.T.G., G.S.A., K.K., K.J.C., R.P.D. and G.T. are employees and shareholders of Regeneron Pharmaceuticals Inc. C.P., N. Fernandez and J.H. are employees and shareholders of Vizgen Inc. The remaining authors declare no competing interests.
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Surgically resected HCC lesions were isolated after two or more doses of PD-1 blockade and analyzed by H&E (N = 20 biologically independent samples) and single-cell RNA sequencing (scRNAseq N = 29 biologically independent samples). (A) Distribution of responders and non-responders across HCC etiologies (Hep B: Hepatitis B; Hep C: Hepatitis C; NASH: Non-alcoholic steatohepatitis; ASH: Alcoholic steatohepatitis). (B) Quantification of immune aggregate areas and numbers stratified by response and T cell infiltration pattern (Two sided T test). (C) Expression of cluster-defining genes by scRNAseq of key immune populations, showing number of UMI per cell. (D) Differences of cluster frequencies between tumor and adjacent tissue (Two-sided T test, adjusted for multiple-hypotheses, Benjamini–Hochberg correction). Dots represent individual study subjects. The box plot center line represents the median; box limits represent the interquartile range (IQR); whiskers represent the minimum and maximum observations greater and lesser than the IQR plus 1.5×IQR, respectively.
Extended Data Fig. 2 Molecular profiling of expanded CD8+ and CD4+ T cell clones associated with response to PD-1 blockade.
Surgically resected HCC lesions were isolated after two or more doses of PD-1 blockade and analyzed by single-cell RNA and TCR sequencing (scRNAseq and scTCRseq, N = 29 and N = 21 biologically independent samples, respectively). (A, B) Expression of cluster-defining gene modules by scRNAseq for (A) CD8+ (B) CD4+ T cell clusters showing number of UMI per cell. (C, D) Cluster frequencies among (C) CD8+ and (D) CD4+ T cells in tumor and adjacent tissue, stratified by response and T cell infiltration pattern. (E) Cluster frequencies among PD-1lo CD8+ T cells in tumor among tumor-enriched clonal T cells and tumor singlet T cells, stratified by response and T cell infiltration pattern. (F) Cluster frequencies among CD4+ T cells in tumor among tumor-enriched clonal T cells and tumor singlet T cells, stratified by response and T cell infiltration pattern. Dots represent individual study subjects. The box plot center line represents the median; box limits represent the interquartile range (IQR); whiskers represent the minimum and maximum observations greater and lesser than the IQR plus 1.5 × IQR, respectively.
Extended Data Fig. 3 Phenotypic distribution among CD8+ T cell clones and clonality assessment in PBMC and tdLN.
(A–C) Phenotypic analysis of clonotype sharing using scTCRseq. (A) Phenotypic distribution of all CD8+ T cell clusters in individual tumor-enriched clones (top 10 per patient) in responders and T cell rich non-responders. (B) Highlight of PD-1hi CD8+ phenotypic distribution for selected CD8+ clones across remaining patients not shown in Fig. 3B. (C) Expression of PD-1hi CD8+ cluster-defining genes by scRNAseq for CD8+ T cells from the selected clones of Fig. 3B for a responder patient, showing number of UMI per cell. (D) BaseScope TCR imaging using DapB (negative control) and PPIB (positive control) in pre-treatment core biopsies, surgical resection and control human tonsils. (E-G) Dynamic TCRseq of tumor lesions, PBMC and tdLN in responders and non-responders. (E) Number of post-treatment tumor-enriched clones present in pre-treatment tumor lesions analyzed using bulk TCRseq, and in PBMC and tdLN analyzed using scTCRseq, across responders and T cell rich non-responders. (F) Percent of post-treatment tumor-enriched clones in PBMC and tdLN, across responders and T cell rich non-responders (N = 7 PBMC and N = 11 tdLN biologically independent samples). (G) Histograms of clone size (number of cells per clone) distribution per patient, stratified by response and T cell infiltration pattern, separately in PBMC and tdLN. Each bar represents an individual clone.
(A, B) CITEseq antibody sequencing analysis of DCs. (A) Expression of DC cluster-defining proteins by showing number of UMI per cell. (B) Gating of CD141 (as a marker of DC1) and CD1c (as a marker of DC2) among resting DC (left) and mregDCs (middle and right). (C–I) Post treatment HCC tissue sections analyzed by MERFISH, multiplex IHC, IF and BaseScope for spatial distribution of T cell subsets and mregDC. (C) MERFISH factor analysis gene scores for selected factors, showing top 10 genes per factor. (D) Quantification of factor activation from (C), defined as average gene expression per cluster. (E) Densities of Progenitor (CD3+CD8+TCF1+ CD45RA-) and naive (CD3+CD8+TCF1+ CD45RA+) CD8+ T cells among T cell rich lesions (N = 12 biologically independent samples. Two-sided T test. Dots represent individual study subjects. The box plot center line represents the median; box limits represent the interquartile range (IQR); whiskers represent the minimum and maximum observations greater and lesser than the IQR plus 1.5 × IQR, respectively). (F) IHC (left) and BaseScope analysis (right) of a representative immune aggregate in responder patient showing CD8+ clones accumulation (N = 1). (G, H) Spatial distribution of mregDC (DCLAMP+), Effector CD8+ T cell (CD3+CD8+TCF1− CD45RA−), Effector CD4+ (CD3+CD8-TCF1− CD45RA−) and CXCL13+ Th (CD3+CD8-TCF1+ CD45RA−), and Progenitor CD8+ (CD3+CD8+TCF1+ CD45RA−) and CXCL13+ Th (CD3+CD8-TCF1+ CD45RA−) in two different responder patients, showing computational rendering of IF with density contour annotation for mregDC (DCLAMP+). (I) Distribution of Progenitor (CD3+CD8+TCF1+ CD45RA−) and Effector (CD3+CD8+TCF1− CD45RA−) CD8+ T cell proximities to mregDC (DCLAMP+), showing histograms of individual cells from a representative responder, vertical gray bars represent the median.
(A–J) Multiplex IF analysis of treatment-naïve HCC lesions (N = 20 biologically independent samples), Surgically resected HCC lesions during treatment with PD-1 blockade (N = 13 biologically independent samples) and HCC tumor biopsies (N = 13 biologically independent samples). (A) Representative images of an mregDC niche, analyzed by IF for T cell markers, in a representative responder (left) and T cell rich non-responder (right). (B) Spatial proximity enrichment analysis of Progenitor CD8+ (CD3+CD8+TCF1+), CXCL13+ Th (CD3+CD8−CXCL13+) and mregDC (DCLAMP+) post-treatment (Two-sided Mann–Whitney U test). (C) Robustness analysis showing spatial proximity patterns across increasing distance thresholds, for pairs and triads post-treatment. (D) Representative images of a niche, analyzed by IF for DC subsets including DC1 (CLEC9A), DC2 (CD1c) and mregDC (DCLAMP). (E) Spatial proximity enrichment analysis showing contact densities (top) and relative enrichment (bottom) at distance of up to 50 µm between Progenitor CD8+ T cell (CD3+CD8+TCF1+) and CXCL13+ Th (CD3+CD8-TCF1+) triads with mregDC (DCLAMP+), DC1 (CLEC9A+) and DC2 (CD1C+), in 6 responders post-treatment. (F-G) Cellular densities of (F) Progenitor CD8+ T cells (CD3+CD8+TCF1+) and CXCL13+ Th (CD3+CD8-CXCL13+) and (G) mregDC (DCLAMP+), DC1 (CLEC9A+) and DC2 (CD1C+) across responders, T cell rich non-responders, pre and post-treatment (Two-sided Mann–Whitney U test). (H) Spatial proximity enrichment analysis of Progenitor CD8+ T cells (CD3+CD8+TCF1+) and mregDC (DCLAMP+) with CXCL13+ Th (CD3+CD8-CXCL13+) or TCF1+ CD4+ T cells (CD3+CD8-TCF1+) in pre-treatment biopsies (Two-sided Mann–Whitney U test). (I) Cellular densities of CXCL13+ Th (CD3+CD8-CXCL13+), TCF1+ CD4+ T cells (CD3+CD8-TCF1+) and Progenitor CD8+ T cells (CD3+CD8+TCF1+) in treatment-naive patients. (J) Spatial proximity enrichment analysis of Progenitor CD8+ T cells (CD3+CD8+TCF1+) and mregDC (DCLAMP+) with CXCL13+ Th (CD3+CD8-CXCL13+) or TCF1+ CD4+ T cells (CD3+CD8-TCF1+) in treatment-naive patients. Dots represent individual study subjects. The box plot center line represents the median; box limits represent the interquartile range (IQR); whiskers represent the minimum and maximum observations greater and lesser than the IQR plus 1.5×IQR, respectively.
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Magen, A., Hamon, P., Fiaschi, N. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat Med 29, 1389–1399 (2023). https://doi.org/10.1038/s41591-023-02345-0
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