ArticlePublisher preview available

A vaccine targeting resistant tumours by dual T cell plus NK cell attack

June 2022
Nature 606(7916):1-7

Authors:

Icahn School of Medicine at Mount Sinai

Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations. A vaccine targeting stress proteins expressed by many cancers blocks a tumour escape mechanism, enabling protective immunity mediated by diverse T cell and NK cell populations.

Efficacy of the MICA/B α3 domain cancer vaccine a, Design of the MICA/B vaccine. pAbs, polyclonal serum IgG. b, MICB-specific serum antibody (Ab) titres quantified by flow cytometry (n = 4 mice per group) in MICB-transgenic mice immunized with Ctrl-vax (blue) or MICB-vax (red). MFI, median fluorescence intensity. c, MICB-specific CD4⁺ T cell responses following immunization with MICB-vax or Ctrl-vax; CFSE dilution of splenocytes stimulated with MICB or control protein (ovalbumin (OVA)); shown are representative flow cytometry plots (left) and quantification for three mice per group (right). d, Cell-surface levels of MICB on B16F10 (MICB) tumours from mice immunized with MICB-vax or Ctrl-vax (n = 4 mice per group); staining of tumour cells with isotype-control monoclonal antibody (grey) or anti-MICA/B monoclonal antibody (specific for the α1–α2 domains, monoclonal antibody not blocked by vaccine-induced antibodies). e, Therapeutic efficacy of MICB-vax (red) or Ctrl-vax (blue) in mice with established B16F10 (MICB) tumours immunized at the indicated time points (n = 7 mice per group). Vax, vaccination. *P = 0.0137, ****P < 0.0001; NS (not significant), P > 0.999. f, g, Vaccine efficacy in two models of spontaneous metastasis. Mice were immunized with Ctrl-vax (blue) or MICB-vax (red) following surgical removal of primary tumours using the B16-B6 melanoma (f; 10 mice per group) or 4T1 breast cancer (g; 13 mice per group) models. Shown are the size of primary tumours at the time of surgery (left), representative images of lung metastases (middle) and quantification of the total number of lung surface metastases (right). D, day; s.c., subcutaneous. h, i, Immunogenicity of the rhesus MICA/B α3 domain vaccine in the rhesus macaque model. h, Timeline of vaccination; blood was drawn 24 h before indicated immunization or boost. i, Serum titres of antibody to rhesus MICA/B for animal ID 9312. Representative data are shown from at least three (b) or two (c–g) independent experiments. Data from a single experiment with technical replicates for each time point are shown in i. Statistical significance was assessed by two-tailed unpaired Student’s t test (b), two-way ANOVA with Sidak’s multiple-comparison test (c), one-way ANOVA with Tukey’s multiple-comparison test (d), two-way ANOVA with Bonferroni’s post hoc test (left) and the log-rank (Mantel–Cox) test (right) (e), two-tailed Mann–Whitney test (f, g) and two-way ANOVA with Tukey’s multiple-comparison test (i). Data are depicted as the mean ± s.e.m. (b–g) or mean ± s.d. (i). Source data

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Vaccine induces T cell and NK cell recruitment into tumours a, Strategy for characterization of tumour-infiltrating immune cells by flow cytometry (FACS) and scRNA-seq. Mice received two immunizations (days 0 and 14), B16F10 (MICB-dox) tumour cells were implanted (day 21), MICB expression was induced on tumour cells by doxycycline treatment (day 28) and tumour-infiltrating immune cells were analysed 7 d later. b–d, Tumour-infiltrating T cell populations following immunization with Ctrl-vax (blue) or MICB-vax (red) (Ctrl-vax, n = 9 mice per group; MICB-vax, n = 10 mice per group; n = 7 mice per group for the γδ T cell panel). Treg cells, regulatory T cells. e, Tumour-infiltrating NK cells (n = 8 mice per group). f, g, Quantification of IFNγ-positive CD4⁺ and CD8⁺ T cells (Ctrl-vax, n = 9 mice per group; MICB-vax, n = 10 mice per group). h, i, UMAP representation of all T cell clusters from scRNA-seq data (h) and the fraction of each T cell subpopulation among total CD45⁺ cells from the experimental group (MICB-vax + doxycycline; red) and three combined control groups (Ctrl-vax ± doxycycline and MICB-vax without doxycycline; blue) (i). DN, double negative. j, k, UMAP representation of NK and ILC1 cells from all experimental groups (j) and the fraction of these subpopulations among total CD45⁺ cells from experimental (red) and combined control (blue) groups (k). l, Fraction of T cells representing expanded clones based on TCR sequence analysis for the experimental group (red) and combined control groups (blue). m, Contribution of CD4⁺ T cells, NK cells and NKG2D receptor to vaccine efficacy. Mice were first immunized with MICB-vax (M) or Ctrl-vax (C) (days 0 and 14) and treated with isotype-control monoclonal antibody (iso), depleting monoclonal antibody (targeting CD4⁺ T cells or NK cells (αCD4 and αNK1.1, respectively)) or NKG2D receptor-blocking monoclonal antibody (αNKG2D) starting on day 21, followed by implantation of B16F10 (MICB) tumour cells (n = 7 mice per group). Representative data from three independent experiments are shown in b–g. scRNA-seq data from a single experiment with sorted CD45⁺ cells pooled from five mice per group are shown in h–l. Representative data from two independent experiments are shown in m. Statistical significance was assessed by two-tailed Mann–Whitney test (b–g) or log-rank (Mantel–Cox) test (m). Data are depicted as the mean ± s.e.m. Source data

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Vaccine retains efficacy against MHC-I-deficient tumours a, b, Comparison of vaccine efficacy against B16F10 (MICB) WT tumours and tumours with resistance mutations in the B2m (a) or Ifngr1 (b) gene. Mice received MICB-vax or Ctrl-vax and were then challenged with tumours of the indicated genotype (n = 7 mice per group). KO, knockout. c, Effect of CD4⁺ T cell and NK cell depletion on immunity to B2m-knockout tumours. Mice were immunized with MICB-vax or Ctrl-vax; treatment with depleting or isotype-control monoclonal antibody was started 2 d before injection of B2m-knockout B16F10 (MICB) tumour cells (n = 7 mice per group). d, Contribution of vaccine-induced anti-MICB antibodies to NK cell-mediated cytotoxicity against B2m-knockout B16F10 (MICB) tumour cells. CFSE-labelled B2m-knockout B16F10 (MICB) tumour cells were pre-incubated with 10 µg per well of purified serum IgG from mice immunized with MICB-vax or Ctrl-vax before the addition of NK cells at different effector to target (E:T) ratios as indicated. The percentage of dead target cells was assessed by flow cytometry. e, Effect of CD4⁺ T cell depletion on vaccine-induced NK cell infiltration into tumours. Flow cytometry quantification of total NK cell numbers is shown in WT (left) and B2m-knockout (right) tumours for the following treatment groups: Ctrl-vax + isotype-control monoclonal antibody (blue), Ctrl-vax + anti-CD4 (orange), MICB-vax + isotype-control monoclonal antibody (red) and MICB-vax + anti-CD4 (green) (n = 7 mice per group). Representative data from two independent experiments are shown in a–e. Statistical significance was assessed by two-way ANOVA with Bonferroni’s post hoc test (left) and log-rank (Mantel–Cox) test (right) (a–c), two-way ANOVA with Sidak’s multiple-comparison test (d) and one-way ANOVA with Tukey’s multiple-comparison test (e). Data are depicted as the mean ± s.e.m. Source data

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Role of CD4⁺ T cells and cDC1 cells in NK cell recruitment to tumours a, Effect of CD4⁺ T cells on migratory DC populations in the tdLNs of mice immunized with MICB-vax versus Ctrl-vax. Total migratory DCs as well as cDC1 and cDC2 cells were quantified 2 d after induction of MICB expression in tumour cells by doxycycline treatment (n = 7 mice per group, except n = 6 for Ctrl-vax without anti-CD4). b, Migratory DC subsets within the tdLN of MICB-vax-immunized mice treated following immunization (days 28 + 30) with isotype-control, CD4-depleting or CD40L-blocking monoclonal antibody (n = 7 mice per group). c, Quantification of DC populations within the tumours of mice immunized with Ctrl-vax (blue) or MICB-vax (red) on day 7 following induction of MICB expression with doxycycline (n = 7 mice per group). d, Effect of cDC1 depletion on MICB vaccine-induced T cell and NK cell accumulation within tumours in Xcr1DTR mice. Mice were treated with DT or left untreated starting on day 26 following immunization with Ctrl-vax or MICB-vax (days 0 + 14) and B16F10 (MICB-dox) tumour implantation (day 21). Immune cells were analysed in tumours 7 d after induction of MICB expression on tumours with doxycycline (day 37) (n = 7 mice per group). e, Contribution of vaccine-induced anti-MICB antibodies to DC-mediated cross-presentation of tumour antigens to CD8⁺ T cells. Bone marrow-derived DCs (BMDCs) were pre-incubated with B2m-knockout B16F10 (MICB-OVA) tumour cells in the presence of affinity-purified serum IgG from mice immunized with Ctrl-vax or MICB-vax at the indicated concentrations. DCs were co-cultured with CFSE-labelled OT-1 CD8⁺ T cells with T cell proliferation as the readout. The role of activating Fc receptor (FcR) was assessed using BMDCs from Fcer1g–/– mice (orange) or pre-incubation of BMDCs with FcR-blocking antibody (yellow) before tumour cell addition. Representative data from two independent experiments are shown in a–e. Statistical significance was assessed by one-way ANOVA with Tukey’s multiple-comparison test (a, b, d), two-tailed Mann–Whitney test (c) and two-way ANOVA with Tukey’s multiple-comparison test (e). Data are depicted as the mean ± s.e.m. (a–d) or mean ± s.d. (e). Source data

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992 | Nature | Vol 606 | 30 June 2022

Article

A vaccine targeting resistant tumours by

dual Tcell plus NK cell attack

Soumya Badrinath1,2, Maxence O. Dellacherie3,4,13, Aileen Li3 ,4,1 0,13 , Shiwei Zheng5,11 ,13,

Xixi Zhang1,2, Miguel Sobral3,4, Jason W. Pyrdol1, Kathryn L. Smith1, Yuheng Lu5,

Sabrina Haag1,2, Hamza Ijaz4, Fawn Connor-Stroud6, Tsuneyasu Kaisho7, Glenn Dranoff8,1 2,

Guo-Cheng Yuan5,11, David J. Mooney3,4 & Kai W. Wucherpfennig1,2,9 ✉

Most cancer vaccines target peptide antigens, necessitating personalization owing

to the vast inter-individual diversity in major histocompatibility complex (MHC)

molecules that present peptides to Tcells. Furthermore, tumours frequently

escape Tcell-mediated immunity through mechanisms that interfere with peptide

presentation1. Here we report a cancer vaccine that induces a coordinated attack

by diverse Tcell and natural killer (NK) cell populations. The vaccine targets the

MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a

result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor

on Tcells and NK cells, but tumours evade immune recognition by proteolytic

MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B

proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance

presentation of tumour antigens by dendritic cells to Tcells and augment the

cytotoxic function of NK cells. Notably, this vaccine maintains ecacy against

MHC class I-decient tumours resistant to cytotoxic Tcells through the

coordinated action of NK cells and CD4+ Tcells. The vaccine is also ecacious in a

clinically important setting: immunization following surgical removal of primary,

highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine

design enables protective immunity even against tumours with common escape

mutations.

We developed a conceptually new cancer vaccine that targets a

tumour immune escape mechanism. The vaccine targets the MICA

and MICB (MICA/B) stress proteins that are upregulated in response

to DNA damage in many types of human cancers but are expressed

at low or undetectable levels by healthy cells

2,3,5,6

. Engagement of

the activating NKG2D receptor by membrane-bound MICA/B trig-

gers the cytotoxicity programme in natural killer (NK) cells and

co-stimulatory signalling in CD8+ Tcells7–9. However, many human

tumours evade this important immune recognition pathway by

proteolytic shedding of MICA/B from the cell surface

4,10–13

. Shed-

ding substantially reduces the surface density on tumour cells of

these immunostimulatory ligands for the NKG2D receptor12,14. Shed

MICA/B proteins have also been reported to induce NKG2D recep-

tor internalization and inhibit NK cell function12,14–16. Patients with

melanoma responding to an autologous cell-based cancer vaccine

(GVAX) plus anti-CTLA-4 were found to develop anti-MICA antibod-

ies, and the presence of these antibodies correlated with reduced

serum levels of shed MICA and augmented CD8

Tcell and NK cell

responses17,18.

Design of the MICA and MICB α3 domain vaccine

Our vaccine targeted the highly conserved α3 domain in MICA/B, the site

of proteolytic shedding, and was designed to induce tumour immunity

by Tcells and NK cells (Fig.1a)19. We intentionally omitted the α1–α2

domains to avoid induction of antibodies that could block NKG2D

receptor binding

. Multivalent display of vaccine antigens greatly

enhances immunogenicity

, and we therefore fused the α3 domain

of MICB or MICA to the N terminus of ferritin from Heliobacter pylori,

which forms particles composed of 24 subunits22 (Extended Data

Fig.1a–c). Ferritin was used as a control antigen in all experiments.

A recently developed mesoporous silica rod (MSR) biodegradable

scaffold formulated with granulocyte-macrophage colony-stimulating

factor (GM-CSF; for dendritic cell (DC) recruitment) and CpG ODN 1826

(adjuvant) was used for vaccine delivery23.

https://doi.org/10.1038/s41586-022-04772-4

Received: 30 July 2021

Accepted: 19 April 2022

Published online: 25 May 2022

Check for updates

1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. 2Department of Immunology, Harvard Medical School, Boston, MA, USA. 3John A. Paulson

School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. 4Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. 5Department

of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA. 6Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA. 7Department of Immunology, Institute of

Advanced Medicine, Wakayama Medical University, Wakayama, Japan. 8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 9Department of Neurology, Brigham

and Women’s Hospital, Boston, MA, USA. 10Present address: Lyell Immunopharma, South San Francisco, CA, USA. 11Present address: Department of Genetics and Genomic Sciences, Charles

Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 12Present address: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

13These authors contributed equally: Maxence O. Dellacherie, Aileen Li, Shiwei Zheng. ✉e-mail: Kai_Wucherpfennig@dfci.harvard.edu

Content courtesy of Springer Nature, terms of use apply. Rights reserved

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Feb 2018
CELL

Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.

Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy

Article

Full-text available

Oct 2016

Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity

Article

Mar 2018

Helping NK cells find their way MICA and MICB proteins can be expressed on tumors and act as “kill me” signals to the immune system. But tumors often disguise themselves by shedding these proteins, which prevents specialized natural killer (NK) cells from recognizing and destroying the cancer. Ferrari de Andrade et al. engineered antibodies directed against the site responsible for the proteolytic shedding of MICA and MICB (see the Perspective by Cerwenka and Lanier). The approach effectively locked MICA and MICB onto tumors so that NK cells could spot them for elimination. The antibodies exhibited preclinical efficacy in multiple tumor models, including humanized melanoma. Furthermore, the strategy reduced lung cancer metastasis after NK cell–mediated tumor lysis. Science , this issue p. 1537 ; see also p. 1460

Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy

Article

May 2017
CANCER CELL

Effector T cells have the capability of recognizing and killing cancer cells. However, whether tumors can become immune resistant through exclusion of effector T cells from the tumor microenvironment is not known. By using a tumor model resembling non-T cell-inflamed human tumors, we assessed whether adoptive T cell transfer might overcome failed spontaneous priming. Flow cytometric assays combined with intra-vital imaging indicated failed trafficking of effector T cells into tumors. Mechanistically, this was due to the absence of CXCL9/10, which we found to be produced by CD103+ dendritic cells (DCs) in T cell-inflamed tumors. Our data indicate that lack of CD103+ DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T cell response, contributing to immune escape.

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Article

Feb 2017

Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

Critical Role for CD103+/CD141+ Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma

Article

Jul 2016

Intratumoral dendritic cells (DC) bearing CD103 in mice or CD141 in humans drive intratumoral CD8(+) T cell activation. Using multiple strategies, we identified a critical role for these DC in trafficking tumor antigen to lymph nodes (LN), resulting in both direct CD8(+) T cell stimulation and antigen hand-off to resident myeloid cells. These effects all required CCR7. Live imaging demonstrated direct presentation to T cells in LN, and CCR7 loss specifically in these cells resulted in defective LN T cell priming and increased tumor outgrowth. CCR7 expression levels in human tumors correlate with signatures of CD141(+) DC, intratumoral T cells, and better clinical outcomes. This work identifies an ongoing pathway to T cell priming, which should be harnessed for tumor therapies.

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Article

Jul 2016

Background Approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. Methods We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti–PD-1 therapy (pembrolizumab) followed by disease progression months to years later. Results Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. Conclusions In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.)

A vaccine targeting resistant tumours by dual T cell plus NK cell attack

Abstract and Figures

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