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De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors

Nature Immunology volume 18, pages 1207–1217 (2017)Cite this article

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Abstract

The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.

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Figure 1: Intratumoral LIGHT remodels angiogenic blood vessels in a dose-dependent manner.
Figure 2: Treatment with LIGHT-VTP induces intratumoral TLSs.
Figure 3: Macrophages and T cells are required for intratumoral TLS formation.
Figure 4: LIGHT-VTP therapy enhances infiltration and tumor-cell killing.
Figure 5: Combined treatment with LIGHT-VTP and immunological-checkpoint blockade increases the survival of RIP1-Tag5 and LLC-bearing mice.
Figure 6: Combined therapy with LIGHT-VTP and checkpoint blockade primes intratumoral effector T cells.
Figure 7: LIGHT-VTP combination immunotherapies enhance therapeutic efficacy.

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Acknowledgements

We thank S. Tanz (The University of Western Australia) for assistance with laser-dissection microscopy; J. Hamzah (Harry Perkins Institute of Medical Research) for the LIGHT expression plasmid; E. Ingley (Harry Perkins Institute of Medical Research) for the pET-44a plasmid containing a tobacco etch virus cleavage site; and D. Hanahan (Swiss Institute for Experimental Cancer Research) for rabbit polyclonal antibody to Tag. Supported by the National Health and Medical Research Council (APP1042446 and APP1122108 to R.G.), the Cancer Council of Western Australia (APP1098579 to R.G.; fellowship to A.J.-P.) and Woodside Energy (fellowship to R.G.).

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Authors and Affiliations

  1. Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia

    Anna Johansson-Percival, Bo He, Zhi-Jie Li, Alva Kjellén, Karen Russell, Ji Li & Ruth Ganss

  2. Centre for Microscopy, Characterization and Analysis, The University of Western Australia, Crawley, Western Australia, Australia

    Irma Larma

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Contributions

A.J.-P., B.H., Z.-J.L., A.K. and I.L. performed experiments and analyzed data; K.R. and J.L. performed experiments; A.J.-P., I.L. and R.G. designed experiments and interpreted data; and A.J.-P. and R.G. wrote the manuscript.

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Correspondence to Ruth Ganss.

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Integrated supplementary information

Supplementary Figure 1 Recombinant LIGHT-VTP induces pericyte contractility and endothelial cell activation.

(a) Western blot showing purification steps for full length murine LIGHT-VTP (CGKRK) protein: (1) protein marker; (2) fusion protein expression in bacterial lysate; (3) column flow through; (4) column washing; (5) eluate from Ni-NTA column; (6) protein after dialysis; (7) released protein after tobacco edge virus (TEV) protease cleavage; (8) purified LIGHT-CGKRK at approximately 20 kDa (boxed); arrow points at bovine serum albumin (BSA) which was added for stability. (b) Histological quantification of CD31+ vessel diameters in untreated mice (n=4), or mice treated bi-weekly for 2 weeks with VTP (n=3) or 20 ng LIGHT-VTP (LV, n=3). **P=0.009, *P=0.003 (Student’s t-test). Scale bar, 50 μm. (c) Histological analysis of ICAM expression in untreated (n=4) and LV treatment groups (n=6). *P=0.003 (Student’s t-test). Scale bar, 50 μm. (d) Immunohistochemical quantification of pericyte (αSMA+) expression of contractile markers (calp, calponin; cald, caldesmon, arrows) and tumor-associated collagen I (col I) in treatment groups. Caldesmon, n=7 untr mice, n=5 LV treated mice; calponin, n=5 untr mice, n=7 LV treated mice; collagen I, n=9 untr mice, n=6 LV treated mice. ***P=0.0001, **P=0.008, *P=0.04, Student’s t-test. Scale bars, 50 μm. Data are presented as means ± s.d. and representative of three independent experiments.

Supplementary Figure 2 CCL21+ TLSs are induced by LIGHT-VTP or transfer of LIGHT-stimulated macrophages.

(a) Histological analysis of LV-induced TLS structures in RIP1-Tag5 tumors before and after laser microdissection and pressure catapulting (LMPC). Scale bar, 100 μm (upper), 150 μm (lower). (b) Immunohistochemical analysis of CCL21 expression in untreated or LV treated tumors in conjunction with MECA79+ HEV (middle) or CD68+ macrophage (right) stainings. Dashed lines show TLS. Depicted are CCL21-positive endothelial cells (arrows), HEV structure (filled arrow head) and macrophages associated with a blood vessel (open arrow head). Scale bar, 50 μm. (c) Relative mRNA in macrophage-depleted, naïve (left) or ConA-activated (right) splenocytes, n=3 C3H donor mice. (d) Schematic presentation of adoptive macrophage transfers (AdT) into tumor-bearing RIP1-Tag5 mice. (e) Quantification of B cells within 100 μm of MECA79+ vessels in tumors after macrophage transfer, *P=0.02, n=3 (Student’s t-test). (f) Histological analysis of CCL21 expression in tumors after transfer of PBS- or LV-stimulated macrophages (PBS MФ, LV MФ), or LV MФ transfer into T cell-depleted mice (αCD4/8). Dashed lines show TLS. Depicted are CCL21-positive endothelial cells (arrows) and macrophages (open arrow heads). Scale bar, 50 μm. Data are presented as mean ± s.d. and are representative of one experiment (c, e, f), two independent (b) and three independent experiments (a).

Supplementary Figure 3 LIGHT-VTP treatment induces infiltration of immune cells into RIP1-Tag5 tumors.

(a) Representative FACS plots showing gating strategy for Fig. 4a including Fluorescence Minus One (FMO) controls. (b) Macroscopic tumor appearance shown for individual RIP1-Tag5 mice at 30 weeks of age, representative images for untreated and LV treatment groups are shown.

Supplementary Figure 4 PDL-1 expression in RIP1-Tag5 tumors and therapeutic effects of checkpoint-blockade treatments.

(a) Histological analysis of PD-L1 expression in untreated RIP1-Tag5 tumors (n=4) and after a 2 week treatment with bi-weekly injections of 20 ng LIGHT-VTP (LV, n=3). Scale bar, 50 μm. Data are presented as mean ± s.d. (b) Survival analysis of RIP1-Tag5 mice treated with LV and control rat IgG2a antibody (n=8), αCTLA-4 (n=6) or αPD-1 (n=5) as single treatment modalities. (c) Macroscopic RIP1-Tag5 tumor appearance after 7 weeks of treatment with LV and control antibodies (LV+control abs) or LV combined with checkpoint inhibitors (LV+αCTLA-4/αPD-1). Representative images from individual mice are shown. Data represent two independent experiments.

Supplementary Figure 5 LIGHT-VTP and checkpoint blockade induce effector T cells in tumors and draining lymph nodes.

(a) Schematic outline of long term treatment of RIP1-Tag5 mice from 23 to 30 weeks with combination therapies. (b) FMO controls for the markers Ki67 and GrzB, representative contour plots. Corresponding data are shown in Fig. 6b. (c) FMO controls for the markers FoxP3 and CD25. Corresponding data are shown in Fig. 6c. (d) FACS quantification of % CD25+ FoxP3+ Treg cells of CD3+ CD4+ T cells in pancreatic tumor-draining lymph nodes of RIP1-Tag5 mice which were left untreated, or treated with LIGHT-VTP and control antibodies (LV+ctrl) or LV+αCTLA-4/αPD-1 antibodies (LV+αCTLA-4/αPD-1), n=3-6 mice (pooled into one group because of limited size of pancreas draining lymph nodes). (e) Ratio of intratumoral Ki67+ GrzB+ CD4+ or CD8+ effector T cells to CD25+ FoxP3+ Treg cells of CD3+ CD4+ T cells, n=4 for all CD4+ T cell analyses, n=5 for CD8+ T cells in LV+ctrl tumors, n=4 for CD8+ T cells in LV αCTLA-4/αPD-1 tumors, *P=0.021, **P=0.001 (Student’s t-test). (f) Quantification of Ki67+ GrzB+ effector CD4+ and CD8+ T cells of CD3+ T cells in tumor-draining lymph nodes from various treatment groups, and representative plots, n=3-6 mice (pooled into one group). Data represent two independent experiments.

Supplementary Figure 6 LIGHT-VTP and checkpoint blockade induce a switch from naive T cells to memory T cells.

(a) FACS quantification of % CD4+ or CD8+ naïve (CD44low CCR7+, upper graph) or memory (CD44+ CCR7-, lower graph) T cells of CD3+ T cells from untreated tumors (n=7), or tumors of LIGHT-VTP+control antibodies (LV+ctrl, n=5) or LV+αCTLA-4/αPD-1 treated mice (n=4 mice), and representative plots. *P=0.05, **P=0.01, Student’s t-test. (b) Quantification of % intratumoral CD4+ or CD8+ proliferating (Ki67+) T cells of memory (CD44+ CCR7-) CD3+ T cells from different treatment groups and representative plots. *P=0.02 (Student’s t-test). (c) FMO controls for CD44 and CCR7, representative FACS plots. (d) FMO controls for CD44, CCR7 and Ki67 stainings, representative FACS plots. Data are presented as mean ± s.d. and represent two independent experiments.

Supplementary Figure 7 LIGHT-VTP combination immunotherapies enhance survival and reduce tumor angiogenesis.

(a) Treatment scheme for bi-weekly LIGHT-VTP (LV) injections combined with adoptive T cell transfers (AdT) or anti-Tag/CpG-ODN vaccine with or without checkpoint blockade. (b) Survival analyses comparing LV+Tag-activated TCR T cell transfer (Tag T) (n=6, mean survival 34±2 weeks) with LV+ConA-activated C3H T cell transfer (ConA T) (n=5, 30±2 weeks). The LV group is shown as reference (original data in Fig. 4d). **P=0.008, *P=0.05 (log-rank test). Data are representative for one experiment. (c) Macroscopic tumor appearance at 29 weeks of age in RIP1-Tag5 groups treated with LV+vaccine or LV triple therapy + vaccine. Representative images from individual mice are shown.

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Johansson-Percival, A., He, B., Li, ZJ. et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. Nat Immunol 18, 1207–1217 (2017). https://doi.org/10.1038/ni.3836

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