Search
Close this search box.

Modeling T cell temporal response to cancer immunotherapy rationalizes development of combinatorial treatment protocols – Nature Cancer

  • Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xia, A., Zhang, Y., Xu, J., Yin, T. & Lu, X.-J. T cell dysfunction in cancer immunity and immunotherapy. Front. Immunol. 10, 1719 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Joncker, N. T. et al. Antigen-independent accumulation of activated effector/memory T lymphocytes into human and murine tumors. Int. J. Cancer 118, 1205–1214 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Raskov, H., Orhan, A., Christensen, J. P. & Gögenur, I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br. J. Cancer 124, 359–367 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McDermott, D. et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat. Rev. 40, 1056–1064 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, J., Ahn, E., Kissick, H. T. & Ahmed, R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For. Immunopathol. Dis. Therap. 6, 7–17 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiang, Y., Li, Y. & Zhu, B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 6, e1792 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brooks, D. G. & Ohashi, P. S. DC1s shield Tpex cells to bolster PD-1 blockade. Immunity 55, 577–579 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20, 218–232 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Humblin, E. et al. Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells. Sci. Immunol. 8, eadg0878 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gill, A. L. et al. PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors. Sci. Immunol. 8, eadg0539 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Christensen, E., Naidas, A., Chen, D., Husic, M. & Shooshtari, P. TMExplorer: a tumour microenvironment single-cell RNAseq database and search tool. PLoS ONE 17, e0272302 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Y. et al. Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell 39, 1578–1593 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Revisiting checkpoint blockade. Nat. Biotechnol. 40, 981 (2022).

  • Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yost, K. E. et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 25, 1251–1259 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bassez, A. et al. A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer. Nat. Med. 27, 820–832 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Caushi, J. X. et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 596, 126–132 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, B. et al. Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer. Nat. Cancer 3, 108–121 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ben-Kiki, O., Bercovich, A., Lifshitz, A. & Tanay, A. Metacell-2: a divide-and-conquer metacell algorithm for scalable scRNA-seq analysis. Genome Biol. 23, 100 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schenkel, J. M. et al. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes. Immunity 54, 2338–2353 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cui, C. et al. Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. Cell 184, 6101–6118.e13 (2021).

  • Gautam, S. et al. The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity. Nat. Immunol. 20, 337–349 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tsui, C. et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature 609, 354–360 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seo, H. et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc. Natl Acad. Sci. USA 116, 12410–12415 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat. Immunol. 20, 890–901 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nandi, D. et al. T cell costimulation, checkpoint inhibitors and anti-tumor therapy. J. Biosci. 45, 50 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kleffel, S. et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242–1256 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, S. et al. Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies. Proc. Natl Acad. Sci. USA 118, e2025570118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bernardo, M. et al. An experimental model of anti-PD-1 resistance exhibits activation of TGFβ and Notch pathways and is sensitive to local mRNA immunotherapy. Oncoimmunology 10, 1881268 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mao, T., Song, E. & Iwasaki, A. PD-1 blockade-driven anti-tumor CD8+ T cell immunity requires XCR1+ dendritic cells. Preprint at bioRxiv https://doi.org/10.1101/2020.04.28.066639 (2020).

  • Garris, C. S. et al. Successful anti-PD-1 cancer immunotherapy requires T cell–dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity 49, 1148–1161 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sánchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Peggs, K. S., Quezada, S. A. & Allison, J. P. Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists. Clin. Exp. Immunol. 157, 9–19 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mayes, P. A., Hance, K. W. & Hoos, A. The promise and challenges of immune agonist antibody development in cancer. Nat. Rev. Drug Discov. 17, 509–527 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chester, C., Sanmamed, M. F., Wang, J. & Melero, I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 131, 49–57 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, G. & Luo, P. Targeting CD137 (4-1BB) towards improved safety and efficacy for cancer immunotherapy. Front. Immunol. 14, 1208788 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, S. et al. Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model. Cancer Immunol. Res. 3, 149–160 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wei, H. et al. Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin. PLoS ONE 8, e84927 (2013).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qu, Q.-X. et al. 4-1BB agonism combined with PD-L1 blockade increases the number of tissue-resident CD8+ T cells and facilitates tumor abrogation. Front. Immunol. 11, 577 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Geuijen, C. et al. A human CD137 × PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nat. Commun. 12, 4445 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leem, G. et al. 4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+ CD8 T cells from primary and metastatic sites of epithelial ovarian cancers. J. Immunother. Cancer 8, e001650 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kallies, A., Zehn, D. & Utzschneider, D. T. Precursor exhausted T cells: key to successful immunotherapy? Nat. Rev. Immunol. 20, 128–136 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chow, A., Perica, K., Klebanoff, C. A. & Wolchok, J. D. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat. Rev. Clin. Oncol. 19, 775–790 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Segal, N. H. et al. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin. Cancer Res. 24, 1816–1823 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cohen, M. et al. The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response. Nat. Cancer 3, 303–317 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yofe, I. et al. Anti-CTLA-4 antibodies drive myeloid activation and reprogram the tumor microenvironment through FcγR engagement and type I interferon signaling. Nat. Cancer 3, 1336–1350 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Salomon, R. et al. Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting. Nat. Cancer 3, 287–302 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Triplett, T. A. et al. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat. Biotechnol. 36, 758–764 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moynihan, K. D. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22, 1402–1410 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yamazaki, C. et al. Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. J. Immunol. 190, 6071–6082 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cha, J.-H., Chang, M. Y., Richardson, J. A. & Eidels, L. Transgenic mice expressing the diphtheria toxin receptor are sensitive to the toxin. Mol. Microbiol. 49, 235–240 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Keren-Shaul, H. et al. MARS-seq2.0: an experimental and analytical pipeline for indexed sorting combined with single-cell RNA sequencing. Nat. Protoc. 14, 1841–1862 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, D. D. & Seung, H. S. Learning the parts of objects by non-negative matrix factorization. Nature 401, 788–791 (1999).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Cai, D., He, X., Han, J. & Huang, T. S. Graph regularized nonnegative matrix factorization for data representation. IEEE Trans. Pattern Anal. Mach. Intell. 33, 1548–1560 (2011).

    Article 
    PubMed 

    Google Scholar
     

  • Hastie, T. & Stuetzle, W. Principal curves. J. Am. Stat. Assoc. 84, 502–516 (1989).

    Article 
    MathSciNet 

    Google Scholar
     

  • Dann, E., Henderson, N. C., Teichmann, S. A., Morgan, M. D. & Marioni, J. C. Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat. Biotechnol. 40, 245–253 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar