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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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“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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Citations
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BackgroundInfluentialTumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
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“As Kras mutant GEMMs are not responsive to checkpoint blockade (3,44), in part due to a low levels of somatic mutations (45), we utilized the murine syngeneic colon adenocarcinoma model MC38.”
BackgroundMethodInfluential
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“CDK4/6 inhibitors also increase tumor infiltration and activation of effector T cells via derepression of NFAT family proteins and their target genes (24), inactivating immunosuppressive cells such as myeloid cells and Tregs (60, 61), and enhancing tumor antigen presentation.”
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“Moreover, chemotherapy plus immunotherapy combinations cause myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) depletion, two fundamental mechanisms in anticancer immunity [26].”
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3D cancer models: One step closer to in vitro human studies
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DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells
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“Increased antigen presentation by tumor cells, stimulation of effector T lymphocyte activation, and decreased proliferation of immunosuppressive Treg cells are among the various mechanisms suggested (64, 65).”
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PD-L2 glycosylation promotes immune evasion and predicts anti-EGFR efficacy
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“Because CULLIN-3SPOP interacts with the PD-L1 cytoplasmic domain, PD-L1 expression is stabilized in tumors treated with CDK4 inhibitors [172].”
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“This allows the assessment of trilaciclib's effects on the host while minimising theoretical concerns related to effects on the tumour.19 In addition to protecting lymphocyte populations and increasing immune activation through differential T-cell recovery, trilaciclib and other CDK4/6 inhibitors have been shown to en…”
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Liao, Z., Yeo, H. L., Wong, S. W., & Zhao, Y. X. (2021) · Biomedicines · doi:10.3390/biomedicines9121769 · Cited by 89
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Two may be better than one: PD-1/PD-L1 blockade combination approaches in metastatic breast cancer
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“CDK4/6i increase PD-L1 expression in vivo, with mounting preclinical data suggesting synergy with PD-1/PD-L1 blockade.(57,59,60,62) For example, in a CT26 model, the clinical activity of abemaciclib was dependent on immunity, and combination anti-PD-L1 plus abemaciclib resulted in superior disease control with complet…”
The immunomodulatory effects of endocrine therapy in breast cancer
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“clear translocation and activity of nuclear factor of activated T cells (NFAT) in T cells, which gave rise to T cell activation and IL-2 production mediated by NFAT signaling [75].”
BackgroundInfluentialHIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species
Nicholson, H. E., Tariq, Z., Housden, B. E., Jennings, R. B., Stransky, L. A., Perrimon, N., Signoretti, S., Harris, I. S., Endress, J. E., & Kaelin, W. G. (2019) · Science Signaling · doi:10.1126/scisignal.aay0482 · Cited by 86
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“…consistent with the observation that CDK4/6 inhibition can stimulate NFAT activity to promote as opposed to inhibit T-cell activation and yield limited effects on proliferation; 56 in this cellular context p38 or other kinases could be initiating RB- phosphorylation which remains poorly understood.”
Cancer-derived sialylated IgG promotes tumor immune escape by binding to Siglecs on effector T cells
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Self-citationOncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
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3D Culture Systems for Exploring Cancer Immunology
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Newly developed 3D in vitro models to study tumor–immune interaction
Mu, P., Zhou, S., Lv, T., Xia, F., Shen, L., Wan, J., Wang, Y., Zhang, H., Cai, S., Peng, J., et al. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02653-w · Cited by 87
“Simultaneous application of PD-1 monoclonal antibodies and CDK4/6 inhibitors also showed enhanced T cell killing of tumor cells [46].”
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“Indeed, it has been demonstrated that CDK4/6i promote tumor microenvironment inflammation, and CD4 + T-cells and/or CD8 + T-cells can in part mediate therapeutic responses (Goel et al., 2017) (Deng et al., 2018) (Jerby-Arnon et al., 2018).”
CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities
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“Moreover, CDK4/6 inhibition was shown to enhance IL2 secretion and activate effector T cells (Deng et al., 2017).”
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“41 42 These findings suggest that therapeutics originally targeting unlimited tumor cell proliferation may also act as immune modulators.”
Applications of human organoids in the personalized treatment for digestive diseases
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“CDK4/6 inhibitor combined with anti-PD-1 blocking antibody treatment of tumor spheres increases the number of infiltrating T cells and enhances antitumor activity.(429) Chimeric antigen receptor T-cell therapy (CAR-T), a new type of cellular immunotherapy, has shown high efficiency and wide clinical application value…”
BackgroundImmune organoids: from tumor modeling to precision oncology
Dao, V. A., Yuki, K., Lo, Y., Nakano, M., & Kuo, C. J. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.06.001 · Cited by 80
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“For example, Deng J et al.(79) discovered that drugs inhibiting cyclin-dependent kinases 4 and 6 (CDK4/6) could increase T-cell activation and facilitate their penetration into tumors.”
BackgroundSHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
Wang, Y., Mohseni, M., Grauel, A., Diez, J. E., Guan, W., Liang, S., Choi, J. E., Pu, M., Chen, D., Laszewski, T., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-80999-x · Cited by 73
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Self-citationCDK4/6 inhibitors: a novel strategy for tumor radiosensitization
Yang, Y., Luo, J., Chen, X., Yang, Z., Mei, X., Ma, J., Zhang, Z., Guo, X., & Yu, X. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01693-w · Cited by 79
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Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts
Xie, Z., Hou, S., Yang, X., Duan, Y., Han, J., Wang, Q., & Liao, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02190 · Cited by 74
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Self-citationCDK4/6 Inhibitors in Melanoma: A Comprehensive Review
Garutti, M., Targato, G., Buriolla, S., Palmero, L., Minisini, A. M., & Puglisi, F. (2021) · Cells · doi:10.3390/cells10061334 · Cited by 75
“Third, CDK4/6 inhibitors significantly increase T-cell activation and functions, directly enhancing anticancer immune functions [77].”
BackgroundMasuda, J., Sakai, H., Tsurutani, J., Tanabe, Y., Masuda, N., Iwasa, T., Takahashi, M., Futamura, M., Matsumoto, K., Aogi, K., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007126 · Cited by 74
Immunomodulatory Roles of Cell Cycle Regulators
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“A substantial IL-2 expression and increased T-cell tumor infiltration was observed in these models and have been connected to the beneficial effect of CDK4 inhibition on antitumoral immunity [90].”
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“T‐cell activation stimulated by palbociclib can be involved in the development of this cutaneous AE, which, although rare, should not be underestimated [37].”
BackgroundAhn, E. R., Mangat, P. K., Garrett-Mayer, E. S., Halabi, S., Dib, E. G., Haggstrom, D. E., Alguire, K. B., Calfa, C. J., Cannon, T. L., Crilley, P. A., et al. (2020) · JCO Precision Oncology · doi:10.1200/po.20.00037 · Cited by 78
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Self-citationThe Tumor Microenvironment in Colorectal Cancer Therapy
Pedrosa, L., Esposito, F. M., Thomson, T. M., & Maurel, J. (2019) · Cancers · doi:10.3390/cancers11081172 · Cited by 73
“CDK4/6 inhibitors have demonstrated activity in combination with CBI in breast and colorectal cancer preclinical models [145,146].”
BackgroundLelliott, E. J., McArthur, G. A., Oliaro, J., & Sheppard, K. E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.661737 · Cited by 65
“In addition to their immune-potentiating effects, inhibitors of CDK4/6 can also dampen immunity via increased expression of PD-L1 on tumor cells (109, 110, 112, 113).”
BackgroundResultInfluentialResistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer
Scheidemann, E. R., & Shajahan‐Haq, A. N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212292 · Cited by 68
“Mice with existing tumors were treated with trilaciclib, a CDK4/6 inhibitor approved for metastatic non-small cell lung cancer, and tumor volume was subsequently measured [99].”
MethodThe Role of CDK4/6 Inhibitors in Breast Cancer
Murphy, C. G. (2019) · Current Treatment Options in Oncology · doi:10.1007/s11864-019-0651-4 · Cited by 64
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Targeting CDK4/6 in breast cancer
Shanabag, A., Armand, J., Son, E., & Yang, H. W. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01395-3 · Cited by 74
“Palbociclib treatment has been shown to increase NFAT nuclear localization and transcriptional activity in T cells, leading to elevated expression of NFAT target genes essential for T cell activation and anti-tumor immunity 124 .”
InfluentialChemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows
Roberts, P. J., Kumarasamy, V. M., Witkiewicz, A. K., & Knudsen, E. S. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-1161 · Cited by 62
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“In addition, an in vitro small-molecule screen identified CDK4/6 inhibitors as capable of directly enhancing T-cell activation via upregulation of NFAT signaling, a family of transcription factors that are required for proper activation and function of T cells (49).”
BackgroundCell Cycle Regulation Meets Tumor Immunosuppression
Li, J., & Stanger, B. Z. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.07.010 · Cited by 64
Sun, W., Zhang, Q., Wang, R., Yang, L., Sun, Y., & Yang, L. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.648687 · Cited by 62
Organoid models of the tumor microenvironment and their applications
Xia, T., Du, W., Chen, X., & Zhang, Y.-N. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16578 · Cited by 63
Self-citationFunctional biology in its natural context: A search for emergent simplicity
Bergelson, J. M., Kreitman, M., Petrov, D. A., Sánchez, Á., & Tikhonov, M. (2021) · eLife · doi:10.7554/elife.67646 · Cited by 59
“We also know now that even targeted cancer therapies impact tumor growth by affecting not just the tumor cells but also the immune system (Deng et al., 2018; Goel et al., 2017).”
BackgroundPrecision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions
Hossain, F. M., Majumder, S., David, J., & Miele, L. (2021) · Cancers · doi:10.3390/cancers13153739 · Cited by 62
“CDK inhibitors (mainly CDK4/6) augment anti-tumor immunity through T-cell activation, supporting the rationale for combination with immunotherapy [108,144,145].”
BackgroundThe current landscape of immunotherapy for pediatric brain tumors
Hwang, E. I., Sayour, E. J., Flores, C., Grant, G. A., Wechsler‐Reya, R. J., Hoang-Minh, L., Kieran, M. W., Salcido, J., Prins, R. M., Figg, J., et al. (2022) · Nature Cancer · doi:10.1038/s43018-021-00319-0 · Cited by 65
O'Sullivan, C. C., Clarke, R. C., Goetz, M. P., & Robertson, J. F. R. (2023) · JAMA Oncology · doi:10.1001/jamaoncol.2023.2000 · Cited by 67
Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer
Asciolla, J. J., Wu, X., Adamopoulos, C., Gavathiotis, E., & Poulikakos, P. I. (2025) · Nature Cancer · doi:10.1038/s43018-024-00893-z · Cited by 66
“…also have a direct immunostimulatory role, as they upregulate T cell receptor (TCR) signaling, nuclear factor NFAT activity and interleukin 2 (IL-2) secretion in T cells, and CDK4/6 inhibitors augmented the response to programmed cell death protein 1 (PD-1) blockade ex vivo and in vivo 142 .”
Shi, A., Kasumova, G. G., Michaud, W. A., Cintolo-Gonzalez, J., Díaz‐Martínez, M., Ohmura, J. F., Mehta, A., Chien, I., Frederick, D. T., Cohen, S., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb3461 · Cited by 59
Self-citationTo Cycle or Fight—CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity
Ameratunga, M., Kipps, E., Okines, A. F. C., & Lopez, J. S. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1999 · Cited by 61
“Effects on cytokine milieu in the tumor microenvironment In addition, Deng and colleagues used a small-molecule screen designed to identify targets that enhanced T-cell activity in the setting of PD-1 engagement and found that CDK4/6 inhibitors potently upregulated IL2 (9).”
BackgroundMethodInfluentialHuemer, F., Leisch, M., Geisberger, R., Melchardt, T., Rinnerthaler, G., Zaborsky, N., & Greil, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082856 · Cited by 60
Hong, L., Aminu, M., Li, S., Lu, X., Petranović, M., Saad, M. B., Chen, P., Qin, K., Varghese, S., Rinsurongkawong, W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36328-z · Cited by 56
Self-citationLee, H., & Hoe, H. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106725 · Cited by 58
Cancer organoids: A platform in basic and translational research
Ma, X., Wang, Q. L., Li, G., Li, H., Xu, S., & Pang, D. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.02.052 · Cited by 62
“Deng et al identified the CDK4/ 6 inhibitor which increased T cell infiltration and had a synergistic action with that of anti-PD-1, thereby improving anti-tumor activity.(178) ALI culture of organoids with a blockade by anti-PD-1 or/and anti-PD-L1 resulted in expansion and activation of tumor antigen-specific T cells.”
BackgroundLuo, L., Yang, P., Mastoraki, S., Rao, X., Wang, Y., Kettner, N. M., Raghavendra, A. S., Tripathy, D., Damodaran, S., Hunt, K. K., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02226-9 · Cited by 59
CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective
Zhou, F. H., Downton, T. D., Freelander, A., Hurwitz, J., Caldon, C. E., & Lim, E. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1148792 · Cited by 58
Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia
Hayashi, Y., Goyama, S., Liu, X., Tamura, M., Asada, S., Tanaka, Y., Fukuyama, T., Wunderlich, M., O'Brien, E. J., Mizukawa, B. E., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12555-1 · Cited by 54
Organoids — Preclinical Models of Human Disease
Ballard, D. H., Boyer, C. J., & Alexander, J. S. (2019) · New England Journal of Medicine · doi:10.1056/nejmc1903253 · Cited by 52
McFaline-Figueroa, J. R., Sun, L., Youssef, G., Huang, R. Y., Li, G., Kim, J., Lee, E. Q., Nayak, L., Chukwueke, U. N., Beroukhim, R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54326-7 · Cited by 58
Phase II Trial of Palbociclib in Patients with Advanced Esophageal or Gastric Cancer
Karasic, T. B., O’Hara, M. H., Teitelbaum, U. R., Damjanov, N., Giantonio, B. J., d’Entremont, T. S., Gallagher, M., Zhang, P. J., & O'Dwyer, P. J. (2020) · The Oncologist · doi:10.1634/theoncologist.2020-0681 · Cited by 53
Biomarkers for Response to Immune Checkpoint Blockade
Ganesan, S., & Mehnert, J. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033604 · Cited by 51
“…suggesting that to other studies that have independently implicated CDK4/6 inhibitors as a potential strategy to increase tumor immunogenicity (Deng et al. 2018, Goel et al. 2017, Schaer et al. 2018, Zhang et al. 2018), and several clinical trials exploring the combination of CDK4 6…”
ResultThe evolution of cyclin dependent kinase inhibitors in the treatment of cancer
Jhaveri, K. L., Burris, H. A., Yap, T. A., Hamilton, E. P., Rugo, H. S., Goldman, J. W., Dann, S. G., Liu, F., Wong, G. Y., Krupka, H. I., et al. (2021) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2021.1944109 · Cited by 56
“Mechanisms include increased tumor cell antigen presentation [147], effector T-cell activation [148,149], and reduced propagation of regulatory T-cells [147].”
Self-citationZhang, J., Liu, X., Zhou, W., Cheng, G., Wu, J., Guo, S., Jia, S., Liu, Y., Li, B., Zhang, X., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-68224-7 · Cited by 51
Organoid co‐culture models of the tumor microenvironment promote precision medicine
Gu, Z., Wu, Q., Shang, B., Zhang, K., & Zhang, W. (2024) · Cancer Innovation · doi:10.1002/cai2.101 · Cited by 47
“Another study used a microfluidic system to screen small molecules that enhance T ‐ cell activity under inhibition of PD ‐ 1 [59].”
BackgroundCyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment
Susanti, N. M. P., & Tjahjono, D. H. (2021) · Molecules · doi:10.3390/molecules26154462 · Cited by 49
“Moreover, trilaciclib exhibits significant potential in defending the bone marrow from the cytotoxic impacts of chemotherapy while enhancing immune activity in patients with TNBC, as well as possibly improving both antitumor safety and efficacy [107].”
BackgroundHan, Y., Xu, S., Ye, W., Wang, Y., Zhang, X., Deng, J., Zhang, Z., Liu, L., & Liu, S. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04297-0 · Cited by 50
“When tumors became palpable, the tumor-bearing mice were treated intraperitoneally with an anti-PD-1 antibody (200 μg/mouse, BioXCell) every 3 days as reported before [21].”
MethodSelf-citationTargeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib
Wander, S. A., O’Brien, N. A., Litchfield, L. M., O’Dea, D., Guimaraes, C. M., Slamon, D. J., & Goel, S. (2022) · The Oncologist · doi:10.1093/oncolo/oyac138 · Cited by 49
Beyond the Cell Cycle: Enhancing the Immune Surveillance of Tumors Via CDK4/6 Inhibition
Chaikovsky, A. C., & Sage, J. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0201 · Cited by 50
“Novel roles for CDK4/6 in immune-relatedmolecular pathways In a related study, Deng and colleagues investigated kinase inhibitors that enhance IL2 secretion, an indicator of T-cell activation, in Jurkat T cells (15).”
BackgroundDavis, A. A., Luo, J. R., Zheng, T., Dai, C., Dong, X., Tan, L., Suresh, R., Ademuyiwa, F. O., Rigden, C. E., Rearden, T. P., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2177 · Cited by 50
“Preclinical data suggest that CDK4/6 i enhances T-cell activation, increases tumor in fi ltration, and may have a synergistic effect with ICI therapy (55).”
Wang, T., Liu, W., Shen, Q., Tao, R., Li, C., Shen, Q., Lin, Y., Huang, Y., Yang, L., Xie, G., et al. (2023) · Cancer Science · doi:10.1111/cas.15961 · Cited by 52
“47 The key antitumor mechanism of action of CDK4/6i is to induce G1 cell cycle arrest by inhibiting phosphorylation of the tumor suppressor RB. 48– 50 However, CDK4/6i can upregulate cyclin D1 expression to further sequester cell cycle inhibitory protein p21, resulting in CDK4/6i resistance.”
BackgroundDiscovery of Small Molecules for the Reversal of T Cell Exhaustion
Marro, B. S., Žák, J., Zavareh, R. B., Teijaro, J. R., Lairson, L. L., & Oldstone, M. B. A. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.119 · Cited by 47
Triple-negative breast cancer: new treatment strategies in the era of precision medicine
Wu, S., Wang, H., Shao, Z., & Jiang, Y. (2020) · Science China Life Sciences · doi:10.1007/s11427-020-1714-8 · Cited by 50
Targeting CDK4/6 for Anticancer Therapy
Qi, J., & Ouyang, Z. (2022) · Biomedicines · doi:10.3390/biomedicines10030685 · Cited by 49
“Natural killer cells and macrophages are major players in the clearance of senescent cells [61,62].”
BackgroundDrug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors
Fogli, S., Re, M. D., Curigliano, G., van Schaik, R. H., Lancellotti, P., & Danesi, R. (2019) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2019.01.006 · Cited by 48
Patnaik, A., Yap, T. A., Chung, H. C., Miguel, M. J. D., Bang, Y., Lin, C., Su, W., Italiano, A., Chow, K. H., Szpurka, A. M., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2821 · Cited by 46
Migliaccio, I., Bonechi, M., McCartney, A., Guarducci, C., Benelli, M., Biganzoli, L., Leo, A. D., & Malorni, L. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102136 · Cited by 50
Maurer, B., Brandstoetter, T., Kollmann, S., Sexl, V., & Prchal‐Murphy, M. (2020) · Haematologica · doi:10.3324/haematol.2020.256313 · Cited by 48
Jérusalem, G., Prat, A., Salgado, R., Reinisch, M., Saura, C., Ruíz-Borrego, M., Nikolinakos, P. G., Ades, F., Filian, J., Huang, N., et al. (2023) · The Breast · doi:10.1016/j.breast.2023.103580 · Cited by 46
Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies
Chen, M., Hu, S., Li, Y., Jiang, T., Jin, H., & Feng, L. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00347-9 · Cited by 47
Cyclin-dependent Kinases as Emerging Targets for Developing Novel Antiviral Therapeutics
Gutiérrez-Chamorro, L., Felip, E., Ezeonwumelu, I. J., Vila, M. M., & Ballana, E. (2021) · Trends in Microbiology · doi:10.1016/j.tim.2021.01.014 · Cited by 46
Abdelmalak, M., Singh, R., Anwer, M. I., Ivanchenko, P., Randhawa, A., Ahmed, M., Ashton, A. W., Du, Y., Jiao, X., & Pestell, R. G. (2022) · Cancers · doi:10.3390/cancers14215388 · Cited by 45
Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer
Zhu, X., Fu, Z., Dutchak, K., Arabzadeh, A., Milette, S., Steinberger, J., Morin, G., Monast, A., Pilon, V., Kong, T., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-1749 · Cited by 46
Immunotherapy in breast cancer: current landscape and emerging trends
Ran, R., Chen, X., Yang, J., & Xu, B. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00667-y · Cited by 60
“Preclinical studies indicated that CDK4/6 inhibitors increased tumor immunogenicity [35] and synergized PD-1 blockade to enhance antitumor efficacy [36, 37].”
Role of senescence induction in cancer treatment
Qin, S., Schulte, B. A., & Wang, G. Y. (2018) · World Journal of Clinical Oncology · doi:10.5306/wjco.v9.i8.180 · Cited by 44
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“Tumor spheroids together with endogenous lymphocyte and myeloid populations could be preserved for short-term (5-9 days) culture, allowing the investigation of endogenous immune–tumor interactions (39, 40).”
BackgroundOut of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis
Cheung, A. H. K., Hui, C. H., Wong, K. Y., Liu, X., Chen, B., Kang, W., & To, K. F. (2022) · International Journal of Cancer · doi:10.1002/ijc.34288 · Cited by 47
“In terms of immune activation, palbociclib has been shown to activate effector T cells and promote their infiltration into the tumor via NFAT and IL2 signaling.(151) The effect is more pronounced when”
BackgroundSelf-citationZhu, B., Cai, Y., Zhou, L., Zhao, L., Chen, J., Shan, X., Sun, X., You, Q., Gong, X., Zhang, W., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-55904-z · Cited by 48
“Abe is also effective in priming anti-tumor immunity with less severe myelosuppression, although prolonged Abe exposure may impair lymphocyte proliferation 39,40 .”
In Vitro Modeling of the Tumor Microenvironment in Tumor Organoids
Devarasetty, M., Forsythe, S. D., Shelkey, E., & Söker, S. (2020) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-020-00258-4 · Cited by 45
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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