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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation
Open accessPublished version of a preprint
Abstract
Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216–33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143. See related article by Jenkins et al., p. 196. This article is highlighted in the In This Issue feature, p. 127
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In the citing paper
“cyclin-dependent kinase inhibitors 4 and 6 (CDK4/6) facilitate T cell activation, resulting in a higher number of tumour-infiltrating T cells in PDOs, cultivated over several days in a microfluidic 3D chip setup.”
From Human disease models in drug development (2023) · cites this paper as [129]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“CDK4/6 inhibition also showed high in vitro and in vivo activity and synergy with anti-PD-1 blocking antibodies129.”
From Human disease models in drug development (2023) · cites this paper as [129]
In the citing paper
“activation of effector T (TEFF) cells upon nuclear factor of activated T cells 1 (NFATC1, best known as NFAT) signaling and interleukin-2 (IL2) secretion (Deng et al., 2018)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Deng et al., 2018
In the citing paper
“CDK4/6 inhibition is also able to stimulate PD-1 expressing T-cells in vitro and enhance T cell infiltration (Deng et al., 2017).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Deng et al., 2017
In the citing paper
“This enhancement is driven at least in part by CDK6-induced phosphorylation of NFAT4.”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Deng et al., 2017
In the citing paper
“Combining palbociclib with a PD-1 blockade enhanced tumor regression and improved overall survival in mouse xenograft models of colon adenocarcinoma (Deng et al., 2017; Zhang et al., 2018).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Deng et al., 2017
In the citing paper
“CDK4/6 inhibitors improved the efficacy of α-PD-1 in murine models by enhancing lymphocyte infiltration and TIL activities [245–248].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [248]
In the citing paper
“We also recently demonstrated that CDK6, but not CDK4, phosphorylates NFAT family transcription factors to promote T cell activation and enhance the anti-tumor immune response[7].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [7]
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“The enhanced immune response upon CDK4/6 inhibition mainly involves the pathway of immune checkpoints [82,83].”
BackgroundRecent progress of CDK4/6 inhibitors’ current practice in breast cancer
Wang, X., Zhao, S., Xin, Q., Zhang, Y., Wang, K., & Li, M. (2024) · Cancer Gene Therapy · doi:10.1038/s41417-024-00747-x · Cited by 174
“Preclinical studies have con fi rmed that CDK4/6i selectively inhibits regulatory T cells (Tregs) and dendritic cells (DC), which can induce immunological tolerance and suppress the immune response [95, 96].”
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Molecular determinants of response to PD-L1 blockade across tumor types
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“Moreover, cyclin-dependent kinase (CDK) inhibitors targeting CDK4 and CDK6 (Goel et al., 2017; Deng et al., 2018), histone deacetylase (HDAC), or DNA methyltransferase inhibitors (Fraga et al.”
BackgroundThe application and prospect of CDK4/6 inhibitors in malignant solid tumors
Du, Q., Guo, X. Y., Wang, M., Li, Y., Sun, X., & Li, Q. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00880-8 · Cited by 150
“CDK6 is an upstream regulatory element of nuclear factor of activated T cells (NFAT), and CDK4/6 inhibitors suppress NFAT phosphorylation, the activation of CTLs, and its ability to kill tumor cells [55].”
BackgroundSelective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs
Yuan, K., Wang, X., Dong, H., Min, W., Hao, H., & Yang, P. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.05.001 · Cited by 148
Senescence as a therapeutically relevant response to CDK4/6 inhibitors
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“This is attributable, at least in part, to inhibition of CDK6-mediated phosphorylation of nuclear factor of activated T cells (NFAT) transcription factors [78, 81].”
BackgroundInfluentialTeh, J. L. F., & Aplin, A. E. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1967 · Cited by 148
“To this end, Deng and colleagues screened for compounds that may enhance T-cell activity utilizing IL2 secretion as a readout (7).”
BackgroundMugarza, E., van Maldegem, F., Boumelha, J., Moore, C., Rana, S., Llorian, M., East, P., Ambler, R., Anastasiou, P., Romero-Clavijo, P., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm8780 · Cited by 144
Patient-Derived Organoids for Precision Cancer Immunotherapy
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“PBMCs were stimulated weekly with autologous tumor organoids in the presence of IL2, and plate-bound anti-CD28 and anti-PD-1 antibodies.”
BackgroundInfluentialSenescence and the tumor-immune landscape: Implications for cancer immunotherapy
Chibaya, L., Snyder, J. T., & Ruscetti, M. A. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.005 · Cited by 146
CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal
Crozier, L., Foy, R., Mouery, B. L., Whitaker, R. H., Corno, A., Spanos, C., Ly, T., Cook, J. G., & Saurin, A. T. (2022) · The EMBO Journal · doi:10.15252/embj.2021108599 · Cited by 142
Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation
Heckler, M., Ali, L. R., Clancy-Thompson, E., Li, Q., Ventre, K. S., Lenehan, P., Roehle, K., Luoma, A., Boelaars, K., Peters, V., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1540 · Cited by 133
“and exposure to CDK4/6 inhibitors (24).”
BackgroundSelf-citationTreatment resistance in diffuse large B-cell lymphoma
He, M. Y., & Kridel, R. (2021) · Leukemia · doi:10.1038/s41375-021-01285-3 · Cited by 134
“elevated IL-2 and interferon γ secretion from T-cells) [127].”
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Self-citationCDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Lelliott, E. J., Kong, I. Y., Zethoven, M., Ramsbottom, K. M., Martelotto, L. G., Meyran, D., Zhu, J. J., Costacurta, M., Kirby, L., Sandow, J. J., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1554 · Cited by 129
Checkpoint inhibitor therapy for metastatic triple-negative breast cancer
Heeke, A. L., & Tan, A. R. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09972-4 · Cited by 131
“Preclinical data have demonstrated synergy between CDK4/6 inhibition and PD-1 blockade [48].”
BackgroundThe link between kidney disease and cancer: complications and treatment
Małyszko, J., Tesařová, P., Capasso, G., & Capasso, A. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30540-7 · Cited by 130
Tumor-on-chip modeling of organ-specific cancer and metastasis
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Adkins, D. R., Ley, J. C., Neupane, P. C., Worden, F. P., Sacco, A. G., Palka, K. A., Grilley‐Olson, J. E., Maggiore, R. J., Salama, N. N., Trinkaus, K. M., et al. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30405-x · Cited by 122
NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1
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Cellular Senescence and the Immune System in Cancer
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Opportunities for Small Molecules in Cancer Immunotherapy
van der Zanden, S. Y., Luimstra, J. J., Neefjes, J., Borst, J., & Ovaa, H. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.04.004 · Cited by 119
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Turning tumors from cold to inflamed to improve immunotherapy response
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“Researchers found upregulated and downregulated transcriptomic signatures driving T-cell exclusion that impacts different molecular processes, such as modulation of cyclin-dependent kinase 4 and 6 (CDK4/6) functions [78].”
BackgroundDirecting Traffic: How to Effectively Drive T Cells into Tumors
Anandappa, A. J., Wu, C. J., & Ott, P. A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0790 · Cited by 113
“CDK4/6 inhibitors like palbociclib have been investigated for their immunostimulatory potential and have been shown to augment T-cell activation and increase T-cell infiltration, via derepression of NFAT activity (88).”
Background3D models in the new era of immune oncology: focus on T cells, CAF and ECM
Modugno, F. D., Colosi, C., Trono, P., Antonacci, G., Ruocco, G., & Nisticò, P. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1086-2 · Cited by 115
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A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib
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“While the key mechanism of action of CDK4/6 inhibitors is to provoke a cell-cycle arrest, they likely contribute clinically relevant antitumoral effects throughmodulation of the immune response (6, 7), induction of senescence (7, 8), or through other noncanonical functions (9).”
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“, 2016) and enhanced activation of tumor-infiltrating T cells (Deng et al., 2018; Schaer et al., 2018).”
Background
Metadata
- Authors
- Deng, J., Wang, E. S., Jenkins, R. W., Li, S., Dries, R., Yates, K., Chhabra, S., Huang, W., Liu, H., Aref, A. R., Ivanova, E., Paweletz, C. P., Bowden, M., Zhou, C. W., Herter-Sprie, G. S., Sorrentino, J. A., Bisi, J. E., Lizotte, P. H., Merlino, A. A., Quinn, M. M., Bufe, L. E., Yang, A., Zhang, Y., Zhang, H., Gao, P., Chen, T., Cavanaugh, M. E., Rode, A. J., Haines, E., Roberts, P. J., Strum, J. C., Richards, W. G., Lorch, J. H., Parangi, S., Gunda, V., Boland, G. M., Bueno, R., Palakurthi, S., Freeman, G. J., Ritz, J., Haining, W. N., Sharpless, N. E., Arthanari, H., Shapiro, G. I., Barbie, D. A., Gray, N. S., & Wong, K.-K.
- Affiliations
- NYU Langone Health (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- 9G1 Therapeutics, Research Triangle Park, North Carolina.
- Brigham and Women's Hospital (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Barbie, David A.
- Gray, Nathanael S.
- Wong, Kwok-Kin
- ORCID
- Deng, Jiehui
- Wang, Eric S.
- Jenkins, Russell W.
- Li, Shuai
- Dries, Ruben
- Yates, Kathleen
- Chhabra, Sandeep
- Huang, Wei
- Liu, Hongye
- Aref, Amir R.
- Ivanova, Elena
- Paweletz, Cloud P.
- Bowden, Michaela
- Zhou, Chensheng W.
- Herter-Sprie, Grit S.
- Sorrentino, Jessica A.
- Bisi, John E.
- Lizotte, Patrick H.
- Yang, Annan
- Zhang, Hua
- Gao, Peng
- Chen, Ting
- Haines, Eric
- Roberts, Patrick J.
- Strum, Jay C.
- Richards, William G.
- Lorch, Jochen H.
- Parangi, Sareh
- Boland, Genevieve M.
- Bueno, Raphael
- Palakurthi, Sangeetha
- Freeman, Gordon J.
- Ritz, Jerome
- Haining, W. Nicholas
- Sharpless, Norman E.
- Arthanari, Haribabu
- Shapiro, Geoffrey I.
- Barbie, David A.
- Gray, Nathanael S.
- Wong, Kwok-Kin
- Venue
- Cancer Discovery
- Published
- 2018-02-01
- Volume
- 8
- Issue
- 2
- Pages
- 216-233
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5809273
- OpenAlex
- W2766016994
- Cited by
- 770
- References
- 63
- Citations by year
- 2026: 62 · 2025: 111 · 2024: 83 · 2023: 109 · 2022: 115 · 2021: 104 · 2020: 96 · 2019: 61 · 2018: 29
- FWCI
- 22.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Damon Runyon Cancer Research Foundation (Damon Runyon) (DRG-2270-16)
- HHS | NIH | National Cancer Institute (NCI) (CA154303-05, CA179483-03, P01CA120964, 5R01CA163896-04, 5R01CA140594-07, 5R01CA122794-10, 5R01CA166480-04)
- Dana-Farber Cancer Institute (DFCI) (Medical Oncology Discovery Grant)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- CDK4/6 inhibitors, antitumor immunity, T cell activation, anti-PD-1 therapy, immune checkpoint blockade, combination immunotherapy, tumor-infiltrating T cells, small-molecule immunomodulators
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Antineoplastic Agents, Humans, Lymphocyte Activation, Neoplasms, T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice
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