The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
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
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838 · cited 12×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundInfluentialNear-optimal probabilistic RNA-seq quantification
Bray, N. L., Pimentel, H., Melsted, P., & Pachter, L. (2016) · Nature Biotechnology · doi:10.1038/nbt.3519 · Cited by 9,723 · cited 11×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundMethodInfluentialNivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., Chow, L. Q., Vokes, E. E., Felip, E., Holgado, E., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1507643 · Cited by 9,335 · cited 11×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundInfluentialMutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., et al. (2015) · Science · doi:10.1126/science.aaa1348 · Cited by 7,802
Pembrolizumab versus Ipilimumab in Advanced Melanoma
Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L., Daud, A., Carlino, M. S., McNeil, C., Lotem, M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1503093 · Cited by 5,887 · cited 11×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundInfluentialTumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., et al. (2002) · Nature Medicine · doi:10.1038/nm730 · Cited by 5,025 · cited 3×
“The discovery of immune checkpoint receptors, such as CTLA-4 and PD-1 (5-9), that repress the activity of anti-tumor T cells, led to the development of blocking antibodies directed against these co-inhibitory receptors or their ligands, including ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), nivolumab (anti-PD1…”
BackgroundNeoantigens in cancer immunotherapy
Schumacher, T. N., & Schreiber, R. D. (2015) · Science · doi:10.1126/science.aaa4971 · Cited by 4,783 · cited 11×
“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
Cited by
Sorted by citations
Items 201–300 of 776
Tan, A. R., Wright, G. S., Thummala, A. R., Danso, M. A., POPOVIC, L. S., Pluard, T., Han, H. S., Vojnović, Ž., Vasev, N., Ma, L., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2272 · Cited by 43
“Additionally, CDK4/6 inhibition modulates T-cell activation by derepressing nuclear factor of activated T-cell family proteins and their target genes, thereby increasing the production of cytokines that enhance immune system function (37).”
BackgroundSelf-citationCDK4/6 nano-PROTAC enhances mitochondria-dependent photodynamic therapy and anti-tumor immunity
Wang, T., Zhang, Y., Chen, K., Huang, Y., Liu, Y., Xu, S., & Wang, W. (2023) · Nano Today · doi:10.1016/j.nantod.2023.101890 · Cited by 42
Self-citationLee, D. H., Imran, M., Choi, J. H., Park, Y. J., Kim, Y. H., Min, S., Park, T. J., & Choi, Y. W. (2023) · Molecular Oncology · doi:10.1002/1878-0261.13541 · Cited by 45
“Nevertheless, recent studies reveal that CDK4/6i treat-ment can elicit anti-tumor immunity by targeting tumor cells and regulatory T cells and can also synergize with immune checkpoint inhibitors [21 – 23].”
BackgroundEffect of radiotherapy on T cell and PD-1 / PD-L1 blocking therapy in tumor microenvironment
Chen, C., Liu, Y., & Cui, B. (2021) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2020.1840254 · Cited by 43
Different sensitivities of senescent breast cancer cells to immune cell‐mediated cytotoxicity
Inao, T., Kotani, H., Iida, Y., Kartika, I. D., Okimoto, T., Tanino, R., Shiba, E., & Harada, M. (2019) · Cancer Science · doi:10.1111/cas.14116 · Cited by 41
Pan‐cancer RNA‐seq data stratifies tumours by some hallmarks of cancer
Frost, F. G., Cherukuri, P. F., Milanovich, S. J., & Boerkoel, C. F. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14746 · Cited by 42
Immunotherapy Targeting PD-1/PD-L1 in Early-Stage Triple-Negative Breast Cancer
Yang, T.-L., Li, W., Huang, T., & Zhou, J. (2023) · Journal of Personalized Medicine · doi:10.3390/jpm13030526 · Cited by 43
“The treatment with CDK4/6 inhibitors activates CD8+ T-cells and heightens the effect of anti-PD-1/PD-L1 agents, indicating the theoretical possibility of the addition of CDK4/6 inhibitors to PD1/PD-L1 antibodies [65,66].”
BackgroundXi, J., & Ma, C. X. (2020) · Current Oncology Reports · doi:10.1007/s11912-020-00917-8 · Cited by 42
Mechanisms and Implications of CDK4/6 Inhibitors for the Treatment of NSCLC
Zhang, J., Xu, D., Zhou, Y., Zhu, Z.-F., & Yang, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.676041 · Cited by 40
“Preclinical research showed that CDK4/6 inhibitors in combination with anti-PDL1 antibodies promote tumor regressions and the effect is accompanied by enhanced antigen presentation, T cell inflamed phenotype, and cytotoxic T cellmediated clearance of lung cancer cells; moreover, this combination improves the overall s…”
BackgroundPD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer
Ali, L. R., Garrido-Castro, A. C., Lenehan, P. J., Böllenrücher, N., Stump, C. T., Dougan, M. L., Goel, S., Shapiro, G. I., Tolaney, S. M., & Dougan, S. K. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20220729 · Cited by 40
“Beyond their effects on cell-cycle progression, they have been shown to function as potent modulators of T cell immunity (Deng et al., 2018; Goel et al., 2017; Schaer et al., 2018; Zhang et al., 2018).”
BackgroundSelf-citationFan, H., Liu, W., Zeng, Y., Zhou, Y., Gao, M., Yang, L., Liu, H., Shi, Y., Li, L., Ma, J., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05412-x · Cited by 39
“In recent years, researchers found that Cdk4 /6 inhibitors not only inhibit cell proliferation, but also trigger anti-tumor immune responses 10 – 12 .”
Self-citationPeuker, C. A., Yaghobramzi, S., Grunert, C., Keilholz, L., Gjerga, E., Hennig, S., Schaper, S., Na, I., Keller, U. B., Brucker, S. Y., et al. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.11.025 · Cited by 41
Engineered in vitro tumor models for cell-based immunotherapy
Ando, Y., Mariano, C. F., & Shen, K. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.03.076 · Cited by 38
Luo, T., Fan, Z., Zeng, A., Wang, A., Pan, Y., Xu, Y., Chen, H., Chen, W., Nie, D., Lin, J., et al. (2024) · Advanced Science · doi:10.1002/advs.202410427 · Cited by 38
Knudsen, E. S., Shapiro, G. I., & Keyomarsi, K. (2020) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_281085 · Cited by 36
Self-citationRoh, W., Geffen, Y., Cha, H., Miller, M. L., Anand, S. K., Kim, J., Heiman, D. I., Gainor, J. F., Laird, P. W., Cherniack, A. D., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0432 · Cited by 37
Getting under the skin: The role of CDK4/6 in melanomas
Guo, L., Qi, J., Wang, H., Jiang, X. L., & Liu, Y. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112531 · Cited by 37
Thanopoulou, E., Khader, L., Caira, M., Wardley, A. M., Ettl, J., Miglietta, F., Neven, P., & Guarneri, V. (2020) · Cancers · doi:10.3390/cancers12113317 · Cited by 37
“Notably, the pharmacological inhibition of CDK4 and 6 was reported to increase in vivo T-cell activation and TIL levels [56].”
BackgroundGoing with the Flow: Modeling the Tumor Microenvironment Using Microfluidic Technology
Xie, H., Appelt, J. W., & Jenkins, R. W. (2021) · Cancers · doi:10.3390/cancers13236052 · Cited by 41
“In the meantime, 3D microfluidic modeling of the TME has demonstrated utility in evaluating novel cancer immunotherapy combinations [58,169,170].”
BackgroundSelf-citationImmune Checkpoint Inhibitors and Novel Immunotherapy Approaches for Breast Cancer
Solís, M. C., Vethencourt, A., & Pernas, S. (2022) · Current Oncology Reports · doi:10.1007/s11912-022-01339-4 · Cited by 38
Integration of immune cells in organs-on-chips: a tutorial
van Os, L., Engelhardt, B., & Guenat, O. T. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1191104 · Cited by 41
“Additionally, T Cells, but not neutrophils, can migrate against the physiological flow in an in vitro flow chamber coated with ICAM-1 and SDF-1 or fMLP (Valignat et al., 2013).”
BackgroundInfluentialEgelston, C. A., Guo, W., Yost, S. E., Lee, J. S., Rose, D. L., Avalos, C., Ye, J., Frankel, P. H., Schmolze, D. D., Waisman, J. R., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002084 · Cited by 36
Various Uses of PD1/PD-L1 Inhibitor in Oncology: Opportunities and Challenges
Li, Z., Sun, G., Sun, G., Cheng, Y., Wu, L., Wang, Q., Lv, C., Zhou, Y., Xia, Y., & Tang, W. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.771335 · Cited by 37
Becherini, C., Visani, L., Caini, S., Bhattacharya, I. S., Kirby, A. M., Marta, G. N., Morgan, G., Salvestrini, V., Coles, C. E., Cortés, J., et al. (2023) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2023.102586 · Cited by 38
CDK4/6 inhibitors in lung cancer: current practice and future directions
Lv, S., Yang, J., Lin, J., Huang, X., Zhao, H., Zhao, C., & Yang, L. (2024) · European Respiratory Review · doi:10.1183/16000617.0145-2023 · Cited by 35
“Pre-clinical studies have shown that the combination of a CDK4/6 inhibitor with an anti-PD-L1 antibody promotes tumour regression, which is accompanied by enhanced antigen presentation, T-cell inflammatory phenotype, and cytotoxic T-cell-mediated lung cancer cell clearance [50, 52].”
BackgroundInfluentialCao, Y., Li, X., Kong, S., Shang, S., & Qi, Y. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15156 · Cited by 35
RetractedSitthideatphaiboon, P., Teerapakpinyo, C., Korphaisarn, K., Leelayuwatanakul, N., Pornpatrananrak, N., Poungvarin, N., Chantranuwat, P., Shuangshoti, S., Aporntewan, C., Chintanapakdee, W., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-06239-y · Cited by 37
Janoštiak, R., Torres-Sanchez, A., Posas, F., & de Nadal, E. (2022) · Cancers · doi:10.3390/cancers14051265 · Cited by 40
Yousuf, M., Alam, M., Shamsi, A., Κhan, P., Hasan, G. M., Haque, Q. M. R., & Hassan, M. I. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.07.156 · Cited by 36
Immunomodulatory effects of CDK4/6 inhibitors
Zhang, S., Xu, Q., Sun, W., Zhou, J., & Zhou, J. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188912 · Cited by 34
Interferon Signaling in Estrogen Receptor–positive Breast Cancer: A Revitalized Topic
Fu, X., Angelis, C. D., & Schiff, R. (2021) · Endocrinology · doi:10.1210/endocr/bqab235 · Cited by 33
Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?
Lelliott, E. J., Sheppard, K. E., & McArthur, G. A. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00273-9 · Cited by 34
Cheng, D., Qiu, K., Rao, Y., Mao, M., Li, L., Wang, Y., Song, Y., Chen, J., Yi, X., Shao, X., et al. (2023) · eLife · doi:10.7554/elife.82705 · Cited by 35
“Cyclindependent kinase 4 (CDK4) inhibitors are introduced as novel drugs by targeting and disrupting the CDK4- related cell cycle progression of cancer cells in recent years (Goel et al., 2018; Deng et al., 2018).”
BackgroundSelf-citationCell Cycle Entry Control in Naïve and Memory CD8+ T Cells
Lewis, D. A., & Ly, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.727441 · Cited by 32
Sollena, P., Nikolaou, V. A., Kotteas, E. A., Stratigos, A., Fattore, D., Orlandi, A., Mannino, M., Pumpo, M. D., Fida, M., Starace, M. V. R., et al. (2023) · Cancers · doi:10.3390/cancers15143658 · Cited by 35
“It is known that CDK4/6i has direct effects on T lymphocytes, with the reduction in T regulatory cells and direct activation of effector T lymphocytes leading to a stronger antitumor immune response [23,24].”
BackgroundHow selective are clinical CDK4/6 inhibitors?
Hendrychová, D., Jorda, R., & Kryštof, V. (2020) · Medicinal Research Reviews · doi:10.1002/med.21769 · Cited by 36
“However, pharmacological CDK4/6 inhibitors enhance the efficacy of immune checkpoint blockage; accordingly, combinatorial treatment using pharmacological CDK4/6 inhibitors with anti‐PD‐1 immunotherapy enhanced tumor regression and improved overall survival in preclinical tumor models.(20,81,84)”
BackgroundInfluentialTumour associated glycans: A route to boost immunotherapy?
Scott, E., Elliott, D. J., & Munkley, J. (2019) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.12.015 · Cited by 31
Inhibition of Haspin Kinase Promotes Cell-Intrinsic and Extrinsic Antitumor Activity
Melms, J. C., Vallabhaneni, S., Mills, C. E., Yapp, C., Chen, J.-Y., Morelli, E., Waszyk, P., Kumar, S., Deming, D., Moret, N., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-2330 · Cited by 33
“Reduction of Tregs mediated by inhibitors of cell cycle or mitosis has been observed in the context of CDK4/6 inhibitors, and may indicate differential yet poorly defined sensitivity of Tregs to antiproliferative compounds (11, 34, 35), including HASPIN inhibitors.”
BackgroundCyclin-dependent kinase inhibitors for the treatment of lung cancer
Qin, A., Reddy, H. G., Weinberg, F. D., & Kalemkerian, G. P. (2020) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2020.1738385 · Cited by 32
Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma
Bröckelmann, P. J., de Jong, M. R. W., & Jachimowicz, R. D. (2020) · Cells · doi:10.3390/cells9102287 · Cited by 31
“This feature of cyclin D1 overexpression is reversed by CDK4 / 6 inhibition, which results in increased antitumor immunity due to enhanced CD8 + T cell infiltration and activity with increased IL-2 secretion in lung cancer mouse models [77].”
BackgroundAdvances in Modeling the Immune Microenvironment of Colorectal Cancer
Yoon, P., Piccolo, N. D., Shirure, V. S., Peng, Y., Kirane, A., Canter, R. J., Fields, R. C., George, S. C., & Gholami, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.614300 · Cited by 33
Combination Approaches to Target PD-1 Signaling in Cancer
Moore, E. K., Strazza, M., & Mor, A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.927265 · Cited by 32
Targeting the Molecular and Immunologic Features of Leiomyosarcoma
Cope, B. M., Traweek, R. S., Lazcano, R., Keung, E. Z.-Y., Lazar, A. J., Roland, C. L., & Nassif, E. F. (2023) · Cancers · doi:10.3390/cancers15072099 · Cited by 33
“CDK4/6 inhibition has been observed to result in greater IL-2 production, which augments antitumor immunity by enhancing T-cell activation and increasing intratumoral T-cell infiltration [98].”
BackgroundCharge and Size Dual Switchable Nanocage for Novel Triple‐Interlocked Combination Therapy Pattern
Yang, R., Zhang, Z., Fu, S., Hou, T., Mu, W., Liang, S., Gao, T., Guan, L., Fang, Y., Liu, Y., et al. (2020) · Advanced Science · doi:10.1002/advs.202000906 · Cited by 31
The RUNX1/RUNX1T1 network: translating insights into therapeutic options
Swart, L. E., & Heidenreich, O. T. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2020.11.005 · Cited by 32
Hot or cold: Bioengineering immune contextures into in vitro patient-derived tumor models
Too, N. S. H., Ho, N. C. W., Adine, C., Iyer, N. G., & Fong, E. L. S. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.05.001 · Cited by 32
Tong, J., Tan, X., Song, X., Gao, M., Risnik, D., Hao, S., Ermine, K., Wang, P., Li, H., Huang, Y., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-3062 · Cited by 32
Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib
Zhu, Z., Turner, N. C., Loi, S., André, F., Martín, M., Dieras, V. C., Gelmon, K. A., Harbeck, N., Zhang, C., Cao, J. Q., et al. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00297-1 · Cited by 40
Lee, J. S., Hackbart, H., Cui, X., & Yuan, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411791 · Cited by 33
“Several stu ies have demonstrated that CDK4/6 inhibitors can enhance antitumor immunity by promoting interferon production, improving tumor antigen presentation, suppressing regulatory T cell proliferation, and increasing tumor infiltration and the activation of effector T cells, thus potentially enhancing the respons…”
BackgroundTumor Milieu Controlled by RB Tumor Suppressor
Kitajima, S., Li, F., & Takahashi, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072450 · Cited by 30
Lee, E. K., Esselen, K. M., Kolin, D. L., Lee, L. J., Matulonis, U. A., & Konstantinopoulos, P. A. (2020) · JCO Precision Oncology · doi:10.1200/po.20.00063 · Cited by 30
“Intratumoral T-cell infiltration increased, at least partly due to upregulated T-cell trafficking chemokines, in the setting of CDK4/6 inhibition.(29,30) Consequently, combination abemaciclib and anti–PD-L1 therapy induced the greatest degree of tumor reduction in murine models of breast cancer compared with monothera…”
BackgroundJang, H.-J., Truong, C., Lo, E. M., Holmes, H. M., Ramos, D., Ramineni, M., Lee, J., Wang, D. Y., Pietropaolo, M., Ripley, R. T., et al. (2021) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2021.08.054 · Cited by 30
Nassif, E. F., Cope, B. M., Traweek, R. S., Witt, R. G., Erstad, D. J., Scally, C. P., Thirasastr, P., Zarzour, M. A., Ludwig, J. A., Benjamin, R. S., et al. (2022) · International Journal of Cancer · doi:10.1002/ijc.33956 · Cited by 30
Siah2 control of T-regulatory cells limits anti-tumor immunity
Scortegagna, M., Hockemeyer, K., Dolgalev, I., Poźniak, J., Rambow, F., Yan, L., Feng, Y., Tinoco, R., Otero, D. C., Zhang, T., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13826-7 · Cited by 29
David, S., Ho, G., Day, D., Harris, M., Tan, J., Goel, S., Hanna, G. G., Srivastava, R., Kruss, G., McDowell, L. J., et al. (2020) · Translational Oncology · doi:10.1016/j.tranon.2020.100939 · Cited by 31
Chen, Y., Jin, Y., Hu, X., & Chen, M. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-021-03895-x · Cited by 30
“Mechanistically, CDK4/6 inhibitors enhance T cell function by upregulating MHC class I and class II expression to increase antigen presentation (Deng et al. 2018; Schaer et al. 2018).”
BackgroundClinical Progress of PD-1/L1 Inhibitors in Breast Cancer Immunotherapy
Chen, F., Chen, N., Gao, Y., Jia, L., Lyu, Z., & Cui, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.724424 · Cited by 31
“Cyclin-dependent kinase (CDK) 4 and 6 inhibitors were demonstrated to be capable of increase levels of tumorinfiltrating T cells and yield synergic antitumor efficacy with antiPD-1/L1 inhibitors in preclinical studies (70, 71).”
BackgroundCarpintero-Fernández, P., Borghesan, M., Eleftheriadou, O., Pan‐Castillo, B., Fafián‐Labora, J., Mitchell, T. P., Yuste, A., Öğrünç, M., Nightingale, T. D., Mayán, M. D., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04569-3 · Cited by 30
Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma
Sager, R., Backe, S. J., Ahanin, E. F., Smith, G., Nsouli, I. S., Woodford, M. R., Bratslavsky, G., Bourboulia, D., & Mollapour, M. (2022) · Nature Reviews Urology · doi:10.1038/s41585-022-00571-8 · Cited by 29
He, R., Yuan, X., Chen, Z., & Zheng, Y. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109444 · Cited by 29
Cellular Senescence in Hepatocellular Carcinoma: The Passenger or the Driver?
Cai, X., Guillot, A., & Liu, H. (2022) · Cells · doi:10.3390/cells12010132 · Cited by 31
Self-citationLiang, J., Sun, G., Pan, X., Zhang, M., Shen, P., Zhu, S., Zhao, J., Zheng, L., Zhao, J., Chen, Y., et al. (2023) · Genome Medicine · doi:10.1186/s13073-023-01182-7 · Cited by 28
“On the other hand, for those without NF2 mutation, cell cycle activation might interfere with PD-1 inhibitor-based immunotherapy, so cell cycle inhibitor combined with PD-1 inhibitor might further improve the efficacy of PD-1 inhibitor-based therapy [42, 43].”
BackgroundNovel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer
Kase, A. M., Copland, J. A., & Tan, W. W. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s266085 · Cited by 30
Pandey, K., Lee, E., Park, N., Hur, J., Cho, Y. B., Katuwal, N. B., Kim, S. K., Lee, S. A., Kim, I., An, H. J., et al. (2021) · Genes · doi:10.3390/genes12020159 · Cited by 26
“Page 12/21 Based on the preclinical evidences that CDK4/6 inhibition augments immune response [18, 19] as mentioned earlier, CDK4/6 inhibitor and immunotherapy combinations have currently been evaluated in a couple clinical trials [39, 40].”
BackgroundSwiecicki, P. L., Durm, G. A., Bellile, E., Bhangale, A. D., Brenner, J. C., & Worden, F. P. (2020) · Investigational New Drugs · doi:10.1007/s10637-020-00898-2 · Cited by 27
“Emerging evidence suggests that CDK 4/6 inhibitors have activity beyond the G1/S checkpoint including induction of dephosphorylation of ATM and CHK1 as well as modulating the immune microenvironment [30].”
BackgroundInflammation and tumor immune escape in response to DNA damage
Nihira, N. T., Kudo, R., & Ohta, T. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.02.005 · Cited by 27
Tumor organoids for cancer research and personalized medicine
Yang, H., Wang, Y., Wang, P., Zhang, N., & Wang, P. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2021.0335 · Cited by 29
Chen, X., Shu, C., Li, W., Hou, Q., Luo, G., Yang, K., & Wu, X. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00063 · Cited by 27
Hargadon, K. M. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04689-9 · Cited by 30
Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy
Zhou, M. Y., Bui, N. Q., Charville, G. W., Ganjoo, K. N., & Pan, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119571 · Cited by 29
“Preclinical studies have shown that abemaciclib activates the expression of endogenous retroviral elements in tumor cells and increases the intracellular level of double-stranded RNA, which stimulates the expression of type-III interferon and increased antigen presentation in the tumor microenvironment [92].”
BackgroundCancer brain metastasis: molecular mechanisms and therapeutic strategies
Lu, Y., Huang, Y., Zhu, C., Li, Z., Zhang, B., Sheng, H., Li, H., Liu, X., Xu, Z., Wen, Y., et al. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00251-0 · Cited by 29
“In vitro small-molecule screen has identified CDK4/6 inhibitors as capable of directly enhancing T-cell activation via NFAT signaling, which was required for proper activation and function of T cells [208].”
Griffiths, J. I., Cosgrove, P. A., Medina, E. F., Nath, A., Chen, J., Adler, F. R., Chang, J. T., Khan, Q. J., & Bild, A. H. (2025) · Nature Communications · doi:10.1038/s41467-025-56279-x · Cited by 29
“This fi nding may be due to the broader effects of ribociclib on immune cells, as it is known that cell cycle inhibitors can cause low white blood cell counts and block T cell proliferation 15,17,74 .”
van Caloen, G., & Machiels, J. (2019) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000513 · Cited by 26
Addressing Resistance to Immune Checkpoint Inhibitor Therapy: An Urgent Unmet Need
Hu‐Lieskovan, S., Malouf, G. G., Jacobs, I. A., Chou, J., Liu, L., & Johnson, M. L. (2021) · Future Oncology · doi:10.2217/fon-2020-0967 · Cited by 26
Wang, B., Li, R., Wu, S., Liu, X., Ren, J., Li, J., Bi, K., Wang, Y., & Jia, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.651541 · Cited by 27
“It was also found that CDK4/6 inhibitors could promote anti-tumor immunity by phosphorylating NFAT4, a transcription factor of T cells, thereby increasing IL-2 levels (91).”
BackgroundDrug induced vitiligo‐like depigmentation from a CDK 4/6 inhibitor
Chan, O. B., Su, J. C., Yazdabadi, A., & Chan, A. (2021) · Asia-Pacific Journal of Clinical Oncology · doi:10.1111/ajco.13585 · Cited by 28
Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing
Qayoom, H., Mehraj, U., Aisha, S., Sofi, S., & Mir, M. A. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.100183 · Cited by 26
Recent advances in targeting protein kinases and pseudokinases in cancer biology
Riegel, K., Vijayarangakannan, P., Kechagioglou, P., Bogucka, K., & Rajalingam, K. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.942500 · Cited by 26
“Combination of CDK4/6 inhibitors and immunotherapy is another strategy to induce anti-cancer immune responses by using anti-PD-1/PD-L1 inhibitors (Deng et al., 2018; Schaer et al., 2018; Yuan et al., 2021).”
BackgroundKim, C. G., Kim, M. H., Kim, J. H., Kim, S., Kim, G. M., Kim, T. Y., Ryu, W., Kim, J. Y., Park, H. S., Park, S., et al. (2023) · Breast Cancer Research · doi:10.1186/s13058-022-01601-4 · Cited by 24
“Moreover, CDK4/6 inhibitors enhance antitumor immunity through tumor infiltration and activation of T cells via transcriptional reprogramming [21, 22].”
BackgroundNayyar, N., de Sauvage, M. A., Chuprin, J., Sullivan, E. M., Singh, M., Torrini, C., Zhang, B. S., Bandyopadhyay, S., Daniels, K. A., Alvarez-Breckenridge, C. A., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0433 · Cited by 26
Schettini, F., Fontana, A., Gattazzo, F., Strina, C., Milani, M., Cappelletti, M. R., Cervoni, V., Morelli, L., Curigliano, G., Iebba, V., et al. (2023) · European Journal of Cancer · doi:10.1016/j.ejca.2023.112948 · Cited by 25
Challenges in validation of combination treatment strategies for CRC using patient-derived organoids
Benboubker, V., Ramzy, G. M., Jacobs, S., & Nowak-Sliwinska, P. M. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03173-x · Cited by 29
“They further validated the combination efficacy in vivo in both partially anti-PD1 responder mouse model (MC38) and anti-PD1 resistant mouse model (CT26) [132].”
BackgroundYao, N., Jing, N., Lin, J., Niu, W., Yan, W., Yuan, H., Xiong, Z., Hou, Q., Qiao, X., Liu, Q., et al. (2025) · Investigational New Drugs · doi:10.1007/s10637-025-01523-w · Cited by 30
“Notably, MDOTS/ PDOTS from immunocompetent murine models or human tumor samples can be established and assessed for 7–14 days [21, 23, 36].”
SMARCA4: Promises and challenges in the treatment of cancers
Ye, W., An, D., & Ou, W. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217811 · Cited by 25
Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy
Li, K., You, J., Wu, Q., Meng, W., He, Q., Yang, B. R., Zhu, C., & Cao, J. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.01.002 · Cited by 26
Hui, R., BOER, R. D., Lim, E., Yeo, B. J., & Lynch, J. (2021) · Asia-Pacific Journal of Clinical Oncology · doi:10.1111/ajco.13555 · Cited by 25
Advanced Acral Melanoma Therapies: Current Status and Future Directions
Zhang, Y., Lan, S., & Wu, D. (2022) · Current Treatment Options in Oncology · doi:10.1007/s11864-022-01007-6 · Cited by 26
Self-citationThe Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery
Bae, J., Choi, Y. S., Cho, G., & Jang, S. J. (2022) · Cancers · doi:10.3390/cancers14092144 · Cited by 27
Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma
Choi, S. H., Chen, Y., Panian, J. A., Yuen, K., & McKay, R. R. (2024) · The Oncologist · doi:10.1093/oncolo/oyae276 · Cited by 27
Giugliano, F., Angelis, C. D., Pistilli, B., Viale, G., Bianchini, G., Giuliano, M., Malorni, L., Salimbeni, B. T., Espósito, A., Giordano, A., et al. (2025) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2025.102980 · Cited by 26
Lelliott, E. J., Mangiola, S., Ramsbottom, K. M., Zethoven, M., Lim, L. R. J., Lau, P. K. H., Oliver, A. J., Martelotto, L. G., Kirby, L., Martin, C., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0401 · Cited by 25
“Similar to BRAF- and MEKtargeted therapies, CDK4/6 inhibitors also have immunomodulatory effects (10, 11).”
BackgroundThe Immunological Role of CDK4/6 and Potential Mechanism Exploration in Ovarian Cancer
Liu, C., Huang, Y., Cui, Y., Zhou, J., Qin, X., Zhang, L., Li, X., Li, Y., Guo, E., Yang, B., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.799171 · Cited by 24
“found that CDK4/6 inhibitors increased the tumor-infiltrating level of T cells in vivo (13).”
BackgroundÇetin, B., Wabl, C. A., & Gümüşay, Ö. (2022) · Future Oncology · doi:10.2217/fon-2021-0842 · Cited by 25
Krysko, D. V., Demuynck, R., Efimova, I., Naessens, F., Krysko, O., & Catanzaro, E. (2022) · Cells · doi:10.3390/cells11223705 · Cited by 26
Shrestha, M., Wang, D., Ben‐David, Y., & Zacksenhaus, E. (2023) · Oncogenesis · doi:10.1038/s41389-023-00475-1 · Cited by 25
The Role and Therapeutic Targeting of CCR5 in Breast Cancer
Hamid, R., Alaziz, M., Mahal, A. S., Ashton, A. W., Halama, N., Jaeger, D., Jiao, X., & Pestell, R. G. (2023) · Cells · doi:10.3390/cells12182237 · Cited by 28
“CDK4/6i increased anti-tumor immunity [122,124] and expression of CCL5 and PD-L1 [125].”
BackgroundAdvances in SHP2 tunnel allosteric inhibitors and bifunctional molecules
Guo, Z., Duan, Y., Sun, K., Zheng, T., Liu, J., Xu, S., & Xu, J. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116579 · Cited by 26
The Emerging Role of Tertiary Lymphoid Structures in Breast Cancer: A Narrative Review
Narvaez, D. P., Nadal, J. C., Nervo, A., Costanzo, M. V., Paletta, C., Petracci, F. E., Rivero, S. G., Ostinelli, A., Freile, B., Enrico, D. H., et al. (2024) · Cancers · doi:10.3390/cancers16020396 · Cited by 23
“In preclinical models, CDK4/6 inhibitors were associated with enhanced tumor antigen presentation, reduced proliferation of regulatory T cells (Tregs), and a lower expression of immune inhibitory receptors, such as PD-1 [50].”
BackgroundSenescence and senolysis in cancer: The latest findings
Imawari, Y., & Nakanishi, M. (2024) · Cancer Science · doi:10.1111/cas.16184 · Cited by 25
Small molecular drugs reshape tumor microenvironment to synergize with immunotherapy
Han, C., Zhang, A., Liu, Z., Moore, C., & Fu, Y. (2020) · Oncogene · doi:10.1038/s41388-020-01575-7 · Cited by 22
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
