c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
30
06
2022
accepted:
08
05
2023
medline:
27
7
2023
pubmed:
20
6
2023
entrez:
19
6
2023
Statut:
ppublish
Résumé
The limited efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we use c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression, but no cell-surface receptor expression, of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen activation-dependent proliferation and CD28- and interleukin-2-independent and interferon-γ-mediated co-stimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in transforming growth factor-β-rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 co-stimulation, KITv co-stimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.
Identifiants
pubmed: 37336986
doi: 10.1038/s43018-023-00573-4
pii: 10.1038/s43018-023-00573-4
doi:
Substances chimiques
CD28 Antigens
0
Interleukin-2
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1001-1015Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA235667
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236615
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214195
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Sadelain, M., Rivière, I. & Riddell, S. Therapeutic T cell engineering. Nature 545, 423–431 (2017).
pubmed: 28541315
pmcid: 5632949
Cappell, K. M. & Kochenderfer, J. N. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat. Rev. Clin. Oncol. 18, 715–727 (2021).
pubmed: 34230645
Grosser, R., Cherkassky, L., Chintala, N. & Adusumilli, P. S. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 36, 471–482 (2019).
pubmed: 31715131
pmcid: 7171534
Kosti, P., Maher, J. & Arnold, J. N. Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors. Front. Immunol. 9, 1104 (2018).
pubmed: 29872437
pmcid: 5972325
Guedan, S. et al. Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability. J. Clin. Invest. 130, 3087–3097 (2020).
pubmed: 32069268
pmcid: 7260017
Wijewarnasuriya, D., Bebernitz, C., Lopez, A. V., Rafiq, S. & Brentjens, R. J. Excessive costimulation leads to dysfunction of adoptively transferred T cells. Cancer Immunol. Res. 8, 732–742 (2020).
pubmed: 32213625
pmcid: 7269815
Drakes, D. J. et al. Optimization of T-cell receptor-modified T cells for cancer therapy. Cancer Immunol. Res. 8, 743–755 (2020).
pubmed: 32209638
pmcid: 7269835
Zuccolotto, G. et al. PSMA-specific CAR-engineered T cells for prostate cancer: CD28 outperforms combined CD28-4-1BB “super-stimulation”. Front. Oncol. 11, 708073 (2021).
pubmed: 34660275
pmcid: 8511814
Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563–571 (2018).
pubmed: 29713085
pmcid: 6117613
Shum, T. et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discov. 7, 1238–1247 (2017).
pubmed: 28830878
pmcid: 5669830
Wang, Y. et al. An IL-4/21 inverted cytokine receptor improving CAR-T cell potency in immunosuppressive solid-tumor microenvironment. Front. Immunol. 10, 1691 (2019).
pubmed: 31379876
pmcid: 6658891
Luo, H. et al. Coexpression of IL7 and CCL21 increases efficacy of CAR-T cells in solid tumors without requiring preconditioned lymphodepletion. Clin. Cancer Res. 26, 5494–5505 (2020).
pubmed: 32816947
Ma, X. et al. Interleukin-23 engineering improves CAR T cell function in solid tumors. Nat. Biotechnol. 38, 448–459 (2020).
pubmed: 32015548
pmcid: 7466194
Hawkins, E. R., D’Souza, R. R. & Klampatsa, A. Armored CAR T-cells: the next chapter in T-cell cancer immunotherapy. Biologics 15, 95–105 (2021).
pubmed: 33883875
pmcid: 8053711
Kagoya, Y. et al. A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects. Nat. Med. 24, 352–359 (2018).
pubmed: 29400710
pmcid: 5839992
Rojas-Sutterlin, S., Lecuyer, E. & Hoang, T. Kit and Scl regulation of hematopoietic stem cells. Curr. Opin. Hematol. 21, 256–264 (2014).
pubmed: 24857885
Ali, S. Role of c-Kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). Gene 401, 38–45 (2007).
pubmed: 17659849
Lennartsson, J. & Rönnstrand, L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol. Rev. 92, 1619–1649 (2012).
pubmed: 23073628
Ceredig, R. & Rolink, T. A positive look at double-negative thymocytes. Nat. Rev. Immunol. 2, 888–897 (2002).
pubmed: 12415312
Bluman, E. M. et al. The c-Kit ligand potentiates the allogeneic mixed lymphocyte reaction. Blood 88, 3887–3893 (1996).
pubmed: 8916954
Frumento, G. et al. CD117 (c-Kit) is expressed during CD8
pubmed: 30930902
pmcid: 6428734
Falchi, L. & Verstovsek, S. Kit mutations: new insights and diagnostic value. Immunol. Allergy Clin. North Am. 38, 411–428 (2018).
pubmed: 30007460
Raghav, P. K., Singh, A. K. & Gangenahalli, G. A change in structural integrity of c-Kit mutant D816V causes constitutive signaling. Mutat. Res. 808, 28–38 (2018).
pubmed: 29482074
Hirota, S. et al. Gain-of-function mutations of c-Kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).
pubmed: 9438854
Longley, B. J. et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat. Genet. 12, 312–314 (1996).
pubmed: 8589724
Beghini, A. et al. c-Kit mutations in core binding factor leukemias. Blood 95, 726–727 (2000).
pubmed: 10660321
Jawhar, M. et al. Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event. Leukemia 29, 1115–1122 (2015).
pubmed: 25567135
Abbaspour Babaei, M., Kamalidehghan, B., Saleem, M., Huri, H. Z. & Ahmadipour, F. Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells. Drug Des. Devel. Ther. 10, 2443–2459 (2016).
pubmed: 27536065
pmcid: 4975146
Omori, I. et al. D816V mutation in the KIT gene activation loop has greater cell-proliferative and anti-apoptotic ability than N822K mutation in core-binding factor acute myeloid leukemia. Exp. Hematol. 52, 56–64 (2017).
pubmed: 28506695
Orfao, A., Garcia-Montero, A. C., Sanchez, L. & Escribano, L., REMA. Recent advances in the understanding of mastocytosis: the role of KIT mutations. Br. J. Haematol. 138, 12–30 (2007).
Xiang, Z., Kreisel, F., Cain, J., Colson, A. & Tomasson, M. H. Neoplasia driven by mutant c-KIT is mediated by intracellular, not plasma membrane, receptor signaling. Mol. Cell. Biol. 27, 267–282 (2007).
pubmed: 17060458
Chaix, A. et al. Mechanisms of STAT protein activation by oncogenic KIT mutants in neoplastic mast cells. J. Biol. Chem. 286, 5956–5966 (2011).
pubmed: 21135090
Harir, N. et al. Oncogenic Kit controls neoplastic mast cell growth through a STAT5/PI3-kinase signaling cascade. Blood 112, 2463–2473 (2008).
pubmed: 18579792
pmcid: 2532813
Larrue, C. et al. Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia. Oncogenesis 8, 39 (2019).
pubmed: 31311917
pmcid: 6635375
Wang, H. et al. The proto-oncogene c-Kit inhibits tumor growth by behaving as a dependence receptor. Mol. Cell 72, 413–425 (2018).
pubmed: 30293784
Adusumilli, P. S. et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6, 261ra151 (2014).
pubmed: 25378643
pmcid: 4373413
Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).
pubmed: 27454297
pmcid: 4966328
Adusumilli, P. S. et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. 11, 2748–2763 (2021).
pubmed: 34266984
pmcid: 8563385
Ghosn, M. et al. Image-guided interventional radiological delivery of chimeric antigen receptor (CAR) T cells for pleural malignancies in a phase I/II clinical trial. Lung Cancer 165, 1–9 (2022).
pubmed: 35045358
Cherkassky, L., Hou, Z., Amador-Molina, A. & Adusumilli, P. S. Regional CAR T cell therapy: an ignition key for systemic immunity in solid tumors. Cancer Cell 40, 569–574 (2022).
pubmed: 35487216
pmcid: 9197990
Nicolet, B. P. et al. CD29 identifies IFN-γ-producing human CD8. Proc. Natl Acad. Sci. USA 117, 6686–6696 (2020).
pubmed: 32161126
pmcid: 7104308
Bhat, P., Leggatt, G., Waterhouse, N. & Frazer, I. H. Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis. 8, e2836 (2017).
pubmed: 28569770
pmcid: 5520949
Smith, K. A. Interleukin-2: inception, impact, and implications. Science 240, 1169–1176 (1988).
pubmed: 3131876
Linnekin, D. Early signaling pathways activated by c-Kit in hematopoietic cells. Int. J. Biochem. Cell Biol. 31, 1053–1074 (1999).
pubmed: 10582339
Xu, Y. et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood 123, 3750–3759 (2014).
pubmed: 24782509
pmcid: 4055922
Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).
pubmed: 21926977
pmcid: 3192229
Ulloa, L., Doody, J. & Massagué, J. Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710–713 (1999).
pubmed: 10067896
Kuga, H. et al. Interferon-γ suppresses transforming growth factor-β-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model. Oncogene 22, 7838–7847 (2003).
pubmed: 14586410
Koh, J. et al. Regulatory (FoxP3
pubmed: 33149213
pmcid: 7642363
Hasegawa, Y. et al. Transforming growth factor-β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer 91, 964–971 (2001).
pubmed: 11251948
Jakubowska, K., Naumnik, W., Niklinska, W. & Chyczewska, E. Clinical significance of HMGB-1 and TGF-β level in serum and BALF of advanced non-small cell lung cancer. Adv. Exp. Med. Biol. 852, 49–58 (2015).
pubmed: 25753556
Urso, L. et al. Detection of circulating immunosuppressive cytokines in malignant pleural mesothelioma patients for prognostic stratification. Cytokine 146, 155622 (2021).
pubmed: 34153874
Stockhammer, P. et al. Detection of TGF-β in pleural effusions for diagnosis and prognostic stratification of malignant pleural mesothelioma. Lung Cancer 139, 124–132 (2020).
pubmed: 31778960
Majzner, R. G. et al. Tuning the antigen density requirement for CAR T-cell activity. Cancer Discov. 10, 702–723 (2020).
pubmed: 32193224
pmcid: 7939454
Feng, Y. et al. A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity. Mol. Cancer Ther. 8, 1113–1118 (2009).
pubmed: 19417159
pmcid: 2891957
Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).
pubmed: 30814732
pmcid: 6546093
Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019).
pubmed: 31802004
pmcid: 6944329
Tripathi, S. K. et al. Genome-wide analysis of STAT3-mediated transcription during early human T
pubmed: 28564606
Seo, H. et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat. Immunol. 22, 983–995 (2021).
pubmed: 34282330
pmcid: 8319109
Fucà, G., Reppel, L., Landoni, E., Savoldo, B. & Dotti, G. Enhancing chimeric antigen receptor T-cell efficacy in solid tumors. Clin. Cancer Res. 26, 2444–2451 (2020).
pubmed: 32015021
pmcid: 7269829
Foster, B. M., Zaidi, D., Young, T. R., Mobley, M. E. & Kerr, B. A. CD117/c-Kit in cancer stem cell-mediated progression and therapeutic resistance. Biomedicines 6, 31 (2018).
pubmed: 29518044
pmcid: 5874688
Pistillo, M. P. et al. IFN-γ upregulates membranous and soluble PD-L1 in mesothelioma cells: potential implications for the clinical response to PD-1/PD-L1 blockade. Cell. Mol. Immunol. 17, 410–411 (2020).
pubmed: 31217525
Chen, N., Li, X., Chintala, N. K., Tano, Z. E. & Adusumilli, P. S. Driving CARs on the uneven road of antigen heterogeneity in solid tumors. Curr. Opin. Immunol. 51, 103–110 (2018).
pubmed: 29554494
pmcid: 5943172
Morello, A., Sadelain, M. & Adusumilli, P. S. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 6, 133–146 (2016).
pubmed: 26503962
Ferrao, P., Gonda, T. J. & Ashman, L. K. Expression of constitutively activated human c-Kit in Myb transformed early myeloid cells leads to factor independence, histiocytic differentiation, and tumorigenicity. Blood 90, 4539–4552 (1997).
pubmed: 9373265
Sepulveda, H., Cerwenka, A., Morgan, T. & Dutton, R. W. CD28, IL-2-independent costimulatory pathways for CD8 T lymphocyte activation. J. Immunol. 163, 1133–1142 (1999).
pubmed: 10415007
Matos, M. E. et al. Expression of a functional c-Kit receptor on a subset of natural killer cells. J. Exp. Med. 178, 1079–1084 (1993).
pubmed: 7688785
Poli, A. et al. CD56
pubmed: 19278419
pmcid: 2673358
Gong, M. C. et al. Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. Neoplasia 1, 123–127 (1999).
pubmed: 10933046
pmcid: 1508130
Krutzik, P. O. & Nolan, G. P. Intracellular phospho-protein staining techniques for flow cytometry: monitoring single cell signaling events. Cytometry A 55, 61–70 (2003).
pubmed: 14505311
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886
Engström, P. G. et al. Systematic evaluation of spliced alignment programs for RNA-seq data. Nat. Methods 10, 1185–1191 (2013).
pubmed: 24185836
pmcid: 4018468