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SCIENCE CHINA Materials, Volume 62 , Issue 11 : 1759-1781(2019) https://doi.org/10.1007/s40843-019-9451-7

Peptide therapeutics and assemblies for cancer immunotherapy

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  • ReceivedApr 26, 2019
  • AcceptedJun 3, 2019
  • PublishedJun 27, 2019

Abstract

Immunotherapy has been considered as one of the most promising strategies for protection against cancer cells due to the tremendous advantages arising from host immune defense. However, establishing versatile strategies with high biosafety and the capability for efficient modulation of immune responses remains challenging. The structural features resembling native proteins of peptides bestow their great potential to address these challenges via either directly eliciting immune responses or improving the efficacy of therapeutics. This review summarizes the progress of cancer immunotherapy achieved based on the strategies utilizing short peptides as therapeutic agents or peptide assemblies as delivery scaffolds, beyond long sequences like proteins and polypeptides. Starting from a brief introduction of cancer immunotherapy, we outline the peptide sequences in terms of their specific functions including immune checkpoint blockades, vaccine antigens and adjuvants. We particularly highlight peptide-based nanomaterials as scaffolds for targeting delivery or co-delivery of multiple therapeutics to enhance immunogenicity. The extraordinary therapeutic efficacy of the limited examples covered here demonstrates the great potency of the peptide-based strategies in modulating immune responses, thus potentially facilitating the clinical translation of cancer immunotherapy in the future.


Funded by

the National Natural Science Foundation of China(21774065)

the Fundamental Research Funds for the Central Universities

and the Natural Science Foundation of Tianjin(18JCQNJC14100)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (21774065), the Fundamental Research Funds for the Central Universities, and the Natural Science Foundation of Tianjin (18JCQNJC14100).


Interest statement

The authors declare no conflict of interest.


Contributions statement

Li M prepared the manuscript under the guidance of Yu Z. Li M and Zhao X designed and prepared the figures. Yu Z and Dai J revised the manuscript. All authors contributed to the general discussion and revision of the manuscript.


Author information

Mingming Li received her Master degree in chemical engineering from China University of Petroleum (Beijing) in 2018. Currently she is a PhD candidate under the supervision of Prof. Zhilin Yu at the Institute of Polymer Chemistry of Nankai University. Her current research interest lies in the field of stimulus-responsive peptide self-assembly and the biomaterials including drug delivery and disease therapy.


Zhilin Yu was awarded his PhD degree under the supervision of Prof. Stefan Hecht at the Humboldt-Universität zu Berlin in 2013. He conducted his postdoctoral training with Prof. Samuel I. Stupp at Northwestern University focusing on self-assembly of peptide-based amphiphilic molecules. In 2017, he started his independent career at the Institute of Polymer Science of Nankai University. His current research interests focus on the self-assembly of peptides into dynamic nanostructures and their broad applications as biomaterials including disease diagnosis and therapy.


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  • Figure 1

    Applications of peptide epitopes or peptide assemblies in cancer immunotherapy ranging from directly serving as therapeutics or as delivery systems for therapeutics.

  • Figure 2

    Schematic illustration of the mechanism of immunotherapy based on inhibition of either the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-mediated immune checkpoint or the programmed cell death protein 1 (PD-1) and its ligand PD-L1 checkpoint.

  • Figure 3

    Schematic representation of immune response pathways for vaccines. Vaccines are up-taken by antigen-presenting cells (APCs) through either endocytosis initiated by binding with Toll-like receptors (TLR) or phagocytosis directly. Degradation of vaccines into short peptides allows for displaying on the surface of APCs via association with major histocompatibility complex (MHC) class I or II receptors.

  • Figure 4

    Peptide assemblies as vaccine adjuvants. (a) Schematic illustration of formation of antigen-displaying peptide nanofibrils and the design of sequences consisting of antigen OVA323–339 and assembling domain Q11. (b) Chemical structures of Q11. TEM images of nanofibrils formed by peptide Q11 (c) and O-Q11 (d). (e) Expression of IgG induced by fibrillized Q11 domains compared to traditional complete Freund’s adjuvant (CFA). (f) Improved secretion of IgG titers induced by OVA, Q11, and O-Q11 in the presence of CFA. *p<0.01. Reproduced with permission from Ref. [106]. Copyright 2010, National Academy of Sciences.

  • Figure 5

    Peptide hydrogels as vaccine adjuvants. (a) Optical and TEM images of hydrogels prepared by phosphatase-induced hydrolysis of Nap-GFFpY-OMe and Nap-GDFDFDpY-OMe in the absence ( L-gel-1, D-gel-1) or presence (L -gel-2, D-gel-2) of antigen OVA. (b) Chemical structures of Nap-GFFpY-OMe and Nap-GDFDFDpY-OMe. (c) The numbers of germinal centers and B-cell follicles induced by different vaccines. (d–h) Production of CD40 (d) and CD86 (e) based on maturation of bone marrow dendritic cells and expression of cytokine IL-6 (f), TNF-α (g), and IL-12 (h) treated with medium (Med) or L-/D-gel vaccines. *p<0.05. Reproduced with permission from Ref. [135]. Copyright 2016, John Wiley and Sons.

  • Figure 6

    Self-assembled antigen amphiphiles. (a) Chemical structure of peptide amphiphile diC16-OVA composed of OVA253–266 and two palmitic tails. Schematic representation of self-assembly of diC16-OVA into cylindrical micelles (b) and their TEM image (c). (d) Production of CD8+ cells induced by different treatments. *p<0.05. Expression of cytokine TLR2 in transfected HEK cells (e), IL-12p40 in DC cells (f), and CD40 in DC cells (g) induced by various treatments. Reproduced with permission from Ref. [87]. Copyright 2012, John Wiley and Sons.

  • Figure 7

    Supramolecular nanomaterials with integrated multiple proteins. (a) Schematic illustration of integration of multiple engineered fusion proteins with a βTail domain into Q11 nanofibers. (b) CD spectra of peptide βTail at different aging times, indicative of the conformational transition from α-helix to β-sheet, as well as CD spectra of Q11 and βTail-mutant. TEM images of self-assemblies of peptide βTail before (c) and after (d) the conformational transition. (e) Antibody polarization towards IgG1 in mice immunized with proteins GFP and cutinase co-fibrillized nanofibers, which is consistent with that immunized with individual protein. Reproduced with permission from Ref. [142]. Copyright 2014, Nature Publishing Group.

  • Figure 8

    Sequentially responsive peptide assemblies for combinatorial anti-PD-L1 and anti-IDO immunotherapy. (a) Chemical structure of DEAP-DPPA-1 consisting of a MMP-2-cleavable fragment PLGLAG as a linker to form the hydrophobic domain and a D-peptide antagonist DPPA-1. (b) Schematic illustration therapeutic mechanism of NLG919@DEAP-DPPA-1 nanoparticles created from assembly of DEAP-DPPA-1 and encapsulation of IDO inhibitor NLG919. Production of CD8+ T cells (c) and IFN-γ-producing cytotoxic T cells (d) induced by immunization of NLG919@DEAP-DPPA-1 nanoparticles in tumors after treated on day 12. Expression of cytokines IFN-γ (e) and IL-2 (f) in mice estimated by ELISA in extracts of isolated tumors 12 days after treatment termination. *p<0.05, **p<0.01, ***p<0.001. Reproduced with permission from Ref. [148]. Copyright 2018, American Chemical Society.

  • Figure 9

    Peptide hydrogels for combinatorial tumor cell antigen and anti-PD-L1 immunotherapy. (a) Schematic representation of the personalized cancer vaccine (PVAX) for postsurgical immunotherapy via simultaneously encapsulating attenuated tumor cells and checkpoint blockades within peptide hydrogels. (b) Chemical structure of Fmoc-KCRGDK (FK) peptide. TEM image of the assemblies of peptide FK after incubation at (c) 37 or (d) 70°C, respectively. Scale bar: 100 nm in (c) and 50 nm in (d). Tumor infiltration (e) and proliferation activity (f) of CD8+ T cells in the recurrent tumors on 10 day after first treatment. (g) Frequency of TNF-α+/IFN-γ+ CD8+ T cells in the recurrent tumor 3 days after first treatment. (h) Ratios of CD8+ T cells to Tregs in the recurrent tumor 10 days after the first treatment. ***p<0.01. Data represent mean±s.d. (n = 3). Reproduced under the terms of the Creative Commons 4.0 license. [149] Copyright 2018, Nature Publishing Group.

  • Figure 10

    Peptide hydrogels for combinatorial DC-based vaccines and anti-PD-1 immunotherapy. (a) Sequence of peptide RADA. (b) Proposed mechanism of the vaccine nodule composed of RADA hydrogels, encapsulated exogenous DCs, tumor antigen, and anti-PD-1 antibody. (c) Average tumor volumes (n = 5) and (d) survival curves (n = 5) of mice after treated with vaccine nodule. Day 0 means the first day of tumor inoculation. **p<0.01. (e) The ratios of CD3+CD8+ T cells in the dLNs and (f) in the spleen of vaccinated mice day 28 after tumor challenge (n = 6). *p<0.05, **p<0.01. Reproduced with permission from Ref. [150]. Copyright 2018, American Chemical Society.

  • Figure 11

    Combinatorial photodynamic therapy and anti-IDO immunotherapy. (a) Chemical structure of peptide PpIX-1MT and schematic illustration of self-assembly of PpIX-1MT into nanoparticles for combinatorial photodynamic therapy and immunotherapy. Ratio of CD4+ T cells to CD3+ lymphocytes (b) or CD3+CD8+ T cells to CD3+CD4+ T cells (c) in mice immunized in different strategies. Flow cytometry analysis of CRT exposure on the CT26 cell surface after incubation with PBS or PpIX-1MT without (d) or with (e) irradiation. Reproduced with permission from Ref. [151]. Copyright 2018, American Chemical Society.

  • Figure 12

    Combinatorial chemotherapy and anti-IDO immunotherapy. (a) Preparation of DOX@MSN-SS-iRGD&1MT and schematic illustration of DOX@MSN-SS-iRGD&1MT for eliciting antitumor immunity against glioblastoma and loading DOX for chemotherapy. (b–e) Immune responses induced by DOX@MSN-SS-iRGD&1MT in vitro: production of CD3+ T cells (b) or cytotoxic CD3+ CD8+ T cells (c) or CD3+ CD4+ T cells (d); (e) Ratio of CD3+ CD4+ T cells to CD3+ CD8+ T cells. *p<0.05 and ***p<0.001. (f–i) Expression of immune cytokines in orthotopic glioma tissue: (f) TNF; (g) IFN γ; (h) IL17; and (i) IL10, in brain glioma tissue detected by ELISA. *p<0.05, **p<0.01, and ***p<0.001. From (b) to (i), 1: PBS; 2: free DOX with 1MT; 3: DOX@MSN-SS-CD; 4: DOX@MSN-SS-iRGD; and 5: DOX@MSN-SS-iRGD&1MT). Reproduced with permission from Ref. [152]. Copyright 2018, John Wiley and Sons.

  • Table 1   Peptide therapeutics in cancer immunotherapy

    Therapeutics

    Name

    Peptide sequences

    Pathway

    Ref.

    PD-1/PD-L1 blockades

    AUNP-12

    (SNTSESF)2KFRVTQ

    -LAPKQIKE-NH2

    PD-1

    [80]

    DPPA-1

    NYSKPTDRQYHF

    PD-L1

    [81]

    DPPA-2

    KHAHHTHNLRLP

    PD-L1

    [81]

    HAC-I

    HVIHEGTVVI

    PD-L1

    [82]

    HAC-V

    HVVHEGTVVI

    PD-L1

    [82]

    TPP-1

    SGQYASYHCWC

    -WRDPGRSGGSK

    PD-L1

    [83]

    PDLong1

    FMTYWHLLN

    -AFTVTVPKDL

    PD-L1

    [84]

    Peptide-57

    Cyclic[F(NMe)ANPHLSWSW

    (NMe)[NLe](NMe)[NLe]R(Scc)]G

    PD-L1

    [85]

    Peptide-71

    Cyclic[F(NMe)F(NMe)[NLe](Sar)

    DV(NMe)FY(Sar)WYL(Scc)]G

    PD-L1

    [85]

    Peptide-99

    Cyclic[FLIVIRDRVFR(Scc)]G

    PD-L1

    [85]

    Peptide antigens

    OVA257–264

    SIINFEKL

    CD8+ T cell

    [86]

    OVA253–266

    EQLESIINFEKLTE

    CD8+ T cell

    [87]

    OVA323–339

    ISQAVHAA

    -HAEINEAGR

    CD8+ T cell

    [88]

    NY-ESO-1

    SLLMWITQV

    CD8+ T cell

    [89]

    MAGE-A3

    FLWGPRALV

    CD8+ T cell

    [90]

    Tyrosinase1–9

    MLLAVLYCL

    CD8+ T cell

    [91]

    Tyrosinase368–376

    YMDGTMSQV

    CD8+ T cell

    [91]

    MART-126–35

    EAAGIGILTV

    CD8+ T cell

    [92]

    gp100280–288

    YLEPGPVTA

    CD8+ T cell

    [93]

    gp100209–217

    IMDQVPFSV

    CD8+ T cell

    [94]

    HGP100

    KVPRNQDWL

    CD8+ T cell

    [95]

    TRP2

    SVYDFFVWL

    CD8+ T cell

    [96]

    Survivin-2B80–88

    AYACNTSTL

    CD8+ T cell

    [97]

    E75

    KIFGSLAFL

    CD8+ T cell

    [98]

    WT1Pep427

    RSDELVRHH

    -NMHQRNMTKL

    CD4+ T cell

    [99]

    E711–20

    YMLDLQPETT

    CD8+ T cell

    [100]

    E786–93

    TLGIVCPI

    CD8+ T cell

    [101]

    E743–57

    GQAEPDRAHYNIVTF

    CD4+, CD8+ T cell

    [102]

    E749–57

    RAHYNIVTF

    CD8+ T cell

    [103]

    E748–54

    PDRAHYNI

    CD4+ T cell

    [104]

    OFA 2

    ALCNTDSPL

    CD4+, CD8+ T cell

    [105]

    Vaccine adjuvants

    Q11

    QQKFQFQFEQQ

    -

    [106]

    KFE8

    FKFEFKFE

    -

    [107]

    Hydrogel

    Nap-GDFDFDYD

    -

    [108]

    Hydrogel

    Nap-GDFDFDYDK

    -

    [109]

    Hydrogel

    GDFDFDY

    -

    [110]

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