Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
Open accessAbstract
Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy.
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
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?
In mouse models, hypoxic zones within tumors lack T cells.
“In mouse models, hypoxic zones within tumors were shown to lack T cells (37, 38).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [38]
High concentrations of oxygen activate the anticancer effects of T cells and NK cells by deactivating the adenosine immunosuppressive microenvironment.
“High concentrations of oxygen activate the anticancer effects of T cells and NK cells by deactivating the adenosine immunosuppressive microenvironment. 127 , 206 , 408”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [127]
Considerable evidence in mouse models has shown that hypoxia promotes tumor escape from immune surveillance and immunotherapy.
“Considerable evidence in mouse models has shown that hypoxia promotes tumor escape from immune surveillance and immunotherapy13–19.”
There are opposite reports showing that tumor hypoxia induces mouse T cell exhaustion and resistance to immunotherapy and depletion of HIF1α increases NK cell activity and tumor infiltration.
“there are also opposite reports showing that tumor hypoxia induces mouse T cell exhaustion and resistance to immunotherapy and depletion of HIF1α increases NK cell activity and tumor infiltration16,17,19,48,49.”
Current studies have focused on the role of hypoxia-induced metabolic reprogramming in causing T cell dysfunction and exhaustion.
“Current studies have focused on the role of hypoxia-induced metabolic reprogramming in causing T cell dysfunction and exhaustion16,19,52–55.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 15,318 · see citing works
The immune contexture in human tumours: impact on clinical outcome
Fridman, W. H., Pagès, F., Sautès-Fridman, C., & Galon, J. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3245 · Cited by 4,981 · see citing works
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R.-A., Reed, K., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302369 · Cited by 4,230 · cited 1× · see citing works
“In clinical trials, more than 50% of metastatic melanoma patients receiving this combination therapy achieved objective clinical responses, with the majority experiencing more than 85% reduction in tumor burden (2).”
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
Hugo, W., Zaretsky, J. M., Sun, L., Song, C., Moreno, B. H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.065 · Cited by 3,448 · see citing works
Targeting hypoxia in cancer therapy
Wilson, W. R., & Hay, M. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3064 · Cited by 3,172 · see citing works
Curran, M. A., Montalvo, W., Yagita, H., & Allison, J. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0915174107 · Cited by 1,874 · see citing works
Self-citationL-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity
Geiger, R., Rieckmann, J. C., Wolf, T., Basso, C., Feng, Y., Fuhrer, T., Kogadeeva, M., Picotti, P., Meissner, F., Mann, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.09.031 · Cited by 1,775 · see citing works
Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1
Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., et al. (2011) · Cell · doi:10.1016/j.cell.2011.07.033 · Cited by 1,595 · see citing works
Kwon, E. D., Drake, C. G., Scher, H. I., Fizazi, K., Bossi, A., van den Eertwegh, A. J. M., Krainer, M., Houede, N., Santos, R., Mahammedi, H., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70189-5 · Cited by 1,511 · see citing works
Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates
Simoni, Y., Becht, E., Fehlings, M., Loh, C. Y., Koo, S.-L., Teng, K. W. W., Yeong, J. P. S., Nahar, R., Zhang, T., Kared, H., et al. (2018) · Nature · doi:10.1038/s41586-018-0130-2 · Cited by 1,370 · see citing works
Royal, R. E., Levy, C. L., Turner, K. M., Mathur, A., Hughes, M. S., Kammula, U. S., Sherry, R. M., Topalian, S. L., Yang, J. C.-H., Lowy, I., et al. (2010) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181eec14c · Cited by 1,266 · see citing works
Corzo, C. A., Condamine, T., Lu, L., Cotter, M. J., Youn, J.-I., Cheng, P., Cho, H.-I., Celis, E., Quiceno, D. G., Padhya, T., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100587 · Cited by 1,173 · see citing works
Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors
Motz, G. T., Santoro, S. P., Wang, L., Garrabrant, T., Lastra, R. R., Hagemann, I. S., Lal, P., Feldman, M. D., Benencia, F., & Coukos, G. (2014) · Nature Medicine · doi:10.1038/nm.3541 · Cited by 1,074 · see citing works
Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected
Marvel, D., & Gabrilovich, D. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80005 · Cited by 1,054 · see citing works
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Sukumar, M., Liu, J., Ji, Y., Subramanian, M., Crompton, J. G., Yu, Z., Roychoudhuri, R., Palmer, D. C., Muranski, P., Karoly, E. D., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69589 · Cited by 952 · see citing works
Myc-driven murine prostate cancer shares molecular features with human prostate tumors
Ellwood‐Yen, K., Graeber, T. G., Wongvipat, J., Iruela‐Arispe, M. L., Zhang, J., Matusik, R. J., THOMAS, G. V., & Sawyers, C. L. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00197-1 · Cited by 816 · see citing works
Detection and Characterization of Tumor Hypoxia Using pO <sub>2</sub> Histography
Vaupel, P., Höckel, M., & Mayer, A. (2007) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1628 · Cited by 728 · see citing works
Scharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.08.009 · Cited by 705 · see citing works
Quezada, S. A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27745 · Cited by 700 · see citing works
Casazza, A., Laoui, D., Wenes, M., Rizzolio, S., Bassani, N., Mambretti, M., Deschoemaeker, S., Ginderachter, J. A. V., Tamagnone, L., & Mazzone, M. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.11.007 · Cited by 627 · see citing works
Immunological mechanisms of the antitumor effects of supplemental oxygenation
Hatfield, S. M., Kjaergaard, J., Lukashev, D., Schreiber, T. H., Belikoff, B., Abbott, R., Sethumadhavan, S., Philbrook, P., Ko, K., Cannici, R., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa1260 · Cited by 600 · see citing works
Metastatic prostate cancer in a transgenic mouse.
Gingrich, J. R., Barrios, R. J., Morton, R. A., Boyce, B. F., DeMayo, F. J., Finegold, M. J., Angelopoulou, R., Rosen, J. M., & Greenberg, N. M. (1996) · PubMed · Cited by 599 · see citing works
Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia
Scharping, N. E., Menk, A. V., Whetstone, R. D., Zeng, X., & Delgoffe, G. M. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0103 · Cited by 520 · see citing works
SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression
Ding, Z., Wu, C., Chu, G. C., Xiao, Y., Ho, D. C., Zhang, J., Perry, S. R., Labrot, E., Wu, X., Lis, R. T., et al. (2011) · Nature · doi:10.1038/nature09677 · Cited by 507 · see citing works
Foster, B. A., Gingrich, J. R., Kwon, E. D., Madias, C. A., & Greenberg, N. M. (1997) · PubMed · Cited by 489 · see citing works
Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype
Gabrusiewicz, K. R., Rodriguez, B. A. T., Wei, J., Hashimoto, Y., Healy, L. M., Maiti, S. N., Thomas, G. A., Zhou, S., Wang, Q., Elakkad, A., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.85841 · Cited by 444 · see citing works
Self-citationHypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer
Chouaı̈b, S., Noman, M. Z., Kosmatopoulos, K., & Curran, M. A. (2016) · Oncogene · doi:10.1038/onc.2016.225 · Cited by 370 · see citing works
Self-citationCD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor
Ye, Q., Song, D.-G., Poussin, M., Yamamoto, T. N., Best, A. J., Li, C., Coukos, G., & Powell, D. J. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0945 · Cited by 324 · see citing works
Hypoxia controls CD4+CD25+ regulatory T‐cell homeostasis via hypoxia‐inducible factor‐1α
Ben‐Shoshan, J., Maysel-Auslender, S., Mor, A., Keren, G., & George, J. (2008) · European Journal of Immunology · doi:10.1002/eji.200838318 · Cited by 260 · see citing works
Combining DNA damaging therapeutics with immunotherapy: more haste, less speed
Brown, J. S., Sundar, R., & Lopez, J. S. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.376 · Cited by 243 · see citing works
Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs
Duan, J.-X., Jiao, H., Kaizerman, J. A., Stanton, T. F., Evans, J., Lan, L., Lorente, G., Banica, M., Jung, D. T., Wang, J., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701028q · Cited by 239 · see citing works
Chiaverotti, T. A., Couto, S. S., Donjacour, A. A., Mao, J., Nagase, H., Cardiff, R. D., Cunha, G. R., & Balmain, A. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2008.070602 · Cited by 228 · see citing works
Curran, M. A., Kim, M., Montalvo-Ortiz, W., Al‐Shamkhani, A., & Allison, J. P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019499 · Cited by 213 · see citing works
Self-citationRagnum, H. B., Vlatkovic, L., Lie, A. K., Axcrona, K., Julin, C. H., Frikstad, K.-A. M., Hole, K. H., Seierstad, T., & Lyng, H. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.604 · Cited by 212 · see citing works
Immune-suppressive properties of the tumor microenvironment
Becker, J. C., Andersen, M. H., Schrama, D., & Straten, P. T. (2013) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-013-1434-6 · Cited by 211 · see citing works
Low dose cyclophosphamide: Mechanisms of T cell modulation
Madondo, M., Quinn, M. A., & Plebanski, M. (2015) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2015.11.005 · Cited by 188 · see citing works
Horton, B. L., Williams, J. B., Cabanov, A., Spranger, S., & Gajewski, T. F. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0249 · Cited by 167 · see citing works
Watson, P. A., Ellwood‐Yen, K., King, J. C., Wongvipat, J., Beau, M. M. L., & Sawyers, C. L. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-3441 · Cited by 156 · see citing works
Tumor Vaccines Expressing Flt3 Ligand Synergize with CTLA-4 Blockade to Reject Preimplanted Tumors
Curran, M. A., & Allison, J. P. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3289 · Cited by 132 · see citing works
Self-citationThe Tumor Microenvironment and Strategies to Improve Drug Distribution
Saggar, J. K., Yu, M., Tan, Q., & Tannock, I. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00154 · Cited by 129 · see citing works
Hypoxia and antitumor CD8+ T cells: An incompatible alliance?
de Silly, R. V., Dietrich, P., & Walker, P. R. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1232236 · Cited by 81 · see citing works
Divergent Effects of Castration on Prostate Cancer in TRAMP Mice: Possible Implications for Therapy
Tang, Y., Wang, L., Goloubeva, O. G., Khan, M. A., Zhang, B., & Hussain, A. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4925 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Macrophages and metabolism in the tumor microenvironment
Vitale, I., Manic, G., Coussens, L. M., Kroemer, G., & Galluzzi, L. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.001 · Cited by 1,837 · see citing works
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01332-8 · Cited by 1,612 · see citing works
The Acidic Tumor Microenvironment as a Driver of Cancer
Boedtkjer, E., & Pedersen, S. F. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034627 · Cited by 1,248 · see citing works
Emami Nejad, A., Najafgholian, S., Rostami, A., Sistani, A., Shojaeifar, S., Esparvarinha, M., Nedaeinia, R., Haghjooy Javanmard, S., Taherian, M., Ahmadlou, M., et al. (2021) · Cancer Cell International · doi:10.1186/s12935-020-01719-5 · Cited by 693 · see citing works
Metabolic barriers to cancer immunotherapy
DePeaux, K., & Delgoffe, G. M. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00541-y · Cited by 618 · see citing works
The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies
Petitprez, F., Meylan, M., de Reyniès, A., Sautès‐Fridman, C., & Fridman, W. H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00784 · Cited by 616 · see citing works
Hypoxia-inducible factors: cancer progression and clinical translation
Wicks, E. E., & Semenza, G. L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci159839 · Cited by 620 · see citing works
Hypoxia signaling in human health and diseases: implications and prospects for therapeutics
Luo, Z., Tian, M., Yang, G., Tan, Q., Chen, Y., Li, G., Zhang, Q., Li, Y., Wan, P., & Wu, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01080-1 · Cited by 499 · see citing works
Therapeutic targeting of the hypoxic tumour microenvironment
Singleton, D. C., Macann, A., & Wilson, W. R. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00539-4 · Cited by 493 · see citing works
The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment
Kim, S. K., & Cho, S. W. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.868695 · Cited by 473 · see citing works
CD8+ T cells in the cancer-immunity cycle
Giles, J. R., Globig, A.-M., Kaech, S. M., & Wherry, E. J. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.005 · Cited by 490 · see citing works
Notch signaling pathway in cancer: from mechanistic insights to targeted therapies
Shi, Q., Xue, C., Zeng, Y., Yuan, X., Chu, Q., Jiang, S., Wang, J., Zhang, Y., Zhu, D., & Li, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01828-x · Cited by 428 · see citing works
Emerging evidence for adapting radiotherapy to immunotherapy
Galluzzi, L., Aryankalayil, M. J., Coleman, C. N., & Formenti, S. C. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00782-x · Cited by 389 · see citing works
Korbecki, J., Grochans, S., Gutowska, I., Barczak, K., & Baranowska‐Bosiacka, I. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207619 · Cited by 378 · see citing works
Mechanisms of Cancer Resistance to Immunotherapy
Bai, R., Chen, N., Li, L., Du, N., Bai, L., Lv, Z., Tian, H., & Cui, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01290 · Cited by 369 · see citing works
Development of Immunotherapy Combination Strategies in Cancer
Yap, T. A., Parkes, E. E., Peng, W., Moyers, J. T., Curran, M. A., & Tawbi, H. A. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1209 · Cited by 344 · see citing works
Self-citationWang, B., Zhao, Q., Zhang, Y., Liu, Z., Zheng, Z., Liu, S., Meng, L., Xin, Y., & Jiang, X. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01820-7 · Cited by 315 · see citing works
Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche
Baldominos, P., Barbera-Mourelle, A., Barreiro, O., Huang, Y., Wight, A. E., Cho, J.-W., Zhao, X., Estivill, G., Adam, I., Sanchez, X., et al. (2022) · Cell · doi:10.1016/j.cell.2022.03.033 · Cited by 318 · see citing works
Targeting signaling pathways in prostate cancer: mechanisms and clinical trials
He, Y., Xu, W., Xiao, Y., Huang, H., Gu, D., & Ren, S. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01042-7 · Cited by 282 · see citing works
Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
Vignali, P. D. A., DePeaux, K., Watson, M. J., Ye, C., Ford, B. R., Lontos, K., McGaa, N. K., Scharping, N. E., Menk, A. V., Robson, S. C., et al. (2023) · Nature Immunology · doi:10.1038/s41590-022-01379-9 · Cited by 269 · see citing works
Hypoxia as a driver of resistance to immunotherapy
Kopecka, J., Salaroglio, I. C., Pérez-Ruiz, E., Sarmento‐Ribeiro, A. B., Saponara, S., Rivas, J. D. L., & Riganti, C. (2021) · Drug Resistance Updates · doi:10.1016/j.drup.2021.100787 · Cited by 261 · see citing works
Luo, Y., Yang, Z., Yu, Y., & Zhang, P. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.10.014 · Cited by 252 · see citing works
CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy
Giuffrida, L., Sek, K., Henderson, M. A., Lai, J., Chen, A. X. Y., Meyran, D., Todd, K. L., Petley, E. V., Mardiana, S., Mølck, C., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23331-5 · Cited by 233 · see citing works
Autophagy in endothelial cells and tumor angiogenesis
Schaaf, M. B. E., Houbaert, D., Meçe, O., & Agostinis, P. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0287-8 · Cited by 231 · see citing works
Tamura, R., Tanaka, T., Akasaki, Y., Murayama, Y., Yoshida, K., & Sasaki, H. (2019) · Medical Oncology · doi:10.1007/s12032-019-1329-2 · Cited by 229 · see citing works
Revisiting Immunotherapy: A Focus on Prostate Cancer
Cha, H.-R., Lee, J. H., & Ponnazhagan, S. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-2948 · Cited by 228 · see citing works
Tumor hypoxia: From basic knowledge to therapeutic implications
Liao, C., Liu, X., Zhang, C., & Zhang, Q. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.12.011 · Cited by 223 · see citing works
Noman, M. Z., Hasmim, M., Lequeux, A., Xiao, M., Duhem, C., Chouaı̈b, S., Berchem, G., & Janji, B. (2019) · Cells · doi:10.3390/cells8091083 · Cited by 215 · see citing works
Ma, S., Zhao, Y., Lee, W. C., Ong, L.-T., Lee, P. L., Jiang, Z., Oguz, G., Niu, Z., Liu, M., Goh, J. Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31764-9 · Cited by 200 · see citing works
Ge, R., Wang, Z., & Liang Cheng, C. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00272-w · Cited by 197 · see citing works
Interfering with Tumor Hypoxia for Radiotherapy Optimization
Telarović, I., Wenger, R. H., & Pruschy, M. N. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02000-x · Cited by 203 · see citing works
Linhares, A. D. S., Battin, C., Jutz, S., Leitner, J. M., Häfner, C., Tobias, J., Wiedermann, U., Kundi, M., Zlabinger, G. J., Grabmeier‐Pfistershammer, K., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-47910-1 · Cited by 185 · see citing works
Hypoxia-induced epithelial to mesenchymal transition in cancer
Hapke, R., & Haake, S. M. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.05.012 · Cited by 184 · see citing works
Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter
Hompland, T., Fjeldbo, C. S., & Lyng, H. (2021) · Cancers · doi:10.3390/cancers13030499 · Cited by 179 · see citing works
Zheng, S., Wang, W., Shen, L., Yao, Y., Xia, W., & Ni, C. (2024) · Experimental Hematology and Oncology · doi:10.1186/s40164-024-00543-1 · Cited by 182 · see citing works
Impact of cancer metabolism on therapy resistance – Clinical implications
Gonçalves, A. C., Richiardone, E., Jorge, J., Polónia, B. R. G., Xavier, C. P. R., Salaroglio, I. C., Riganti, C., Vasconcelos, M. H., Corbet, C., & Sarmento‐Ribeiro, A. B. (2021) · Drug Resistance Updates · doi:10.1016/j.drup.2021.100797 · Cited by 170 · see citing works
Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy
Li, Y., Zhao, L., & Li, X.-F. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.700407 · Cited by 168 · see citing works
Wang, S., Wu, Q., Chen, T., Su, R., Pan, C., Qian, J., Huang, H., Yin, S., Xie, H., Zhou, L., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.03.011 · Cited by 168 · see citing works
Luo, Z., Xia, K., Liu, Y.-W., Liu, J., Rao, S., Hu, X., Chen, C., Xu, R., Wang, Z., & Xie, H. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s304515 · Cited by 167 · see citing works
Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications
Testa, U., Castelli, G., & Pelosi, E. (2019) · Medicines · doi:10.3390/medicines6030082 · Cited by 168 · see citing works
Antonarakis, E. S., Park, S. H., Goh, J. C. H., Shin, S. J., Lee, J., Mehra, N., McDermott, R., Sala‐González, N., Fong, P. C. C., Greil, R., et al. (2023) · Journal of Clinical Oncology · doi:10.1200/jco.23.00233 · Cited by 153 · see citing works
Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications
Shi, R., Liao, C., & Zhang, Q. H. (2021) · Cells · doi:10.3390/cells10030678 · Cited by 151 · see citing works
Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer
El-Kenawi, A., Gatenbee, C., Robertson‐Tessi, M., Bravo, R., Dhillon, J., Balagurunathan, Y., Berglund, A., Vishvakarma, N. K., Ibrahim‐Hashim, A., Choi, J. W., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0542-2 · Cited by 147 · see citing works
Devi, S., Alexandre, Y. O., Loi, J. K., Gillis, R. D., Ghazanfari, N., Creed, S. J., Holz, L. E., Shackleford, D. M., Mackay, L. K., Heath, W. R., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.03.025 · Cited by 142 · see citing works
Role of hypoxia in the tumor microenvironment and targeted therapy
Chen, G., Wu, K., Li, H., Xia, D., & He, T. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.961637 · Cited by 141 · see citing works
Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils
Mahiddine, K., Blaisdell, A., Ma, S., Créquer-Grandhomme, A., Lowell, C. A., & Erlebacher, A. (2019) · Journal of Clinical Investigation · doi:10.1172/jci130952 · Cited by 140 · see citing works
Targeting myeloid-derived suppressor cells to enhance natural killer cell-based immunotherapy
Joshi, S., & Sharabi, A. B. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108114 · Cited by 143 · see citing works
Interpretable systems biomarkers predict response to immune-checkpoint inhibitors
Lapuente-Santana, Ó., van Genderen, M. N. G., Hilbers, P. A. J., Finotello, F., & Eduati, F. (2021) · Patterns · doi:10.1016/j.patter.2021.100293 · Cited by 142 · see citing works
Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors
Park, J. H., Kim, H.-J., Kim, C. W., Kim, H. C., Jung, Y., Lee, H., Lee, Y., Ju, Y. S., Oh, J. E., Park, S., et al. (2021) · Nature Immunology · doi:10.1038/s41590-020-00860-7 · Cited by 137 · see citing works
Hossain, M. A., Liu, G., Dai, B., Si, Y., Yang, Q., Wazir, J., Birnbaumer, L., & Yang, Y. (2020) · Medicinal Research Reviews · doi:10.1002/med.21727 · Cited by 137 · see citing works
Beyond the Barrier: Unraveling the Mechanisms of Immunotherapy Resistance
Bell, H. N., & Zou, W. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101819-024752 · Cited by 134 · see citing works
Unraveling tumor microenvironment of small-cell lung cancer: Implications for immunotherapy
Li, T. X., & Qiao, T. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.09.005 · Cited by 131 · see citing works
T cell exhaustion in malignant gliomas
Watowich, M., Gilbert, M. R., & Larion, M. (2023) · Trends in cancer · doi:10.1016/j.trecan.2022.12.008 · Cited by 140 · see citing works
Lequeux, A., Noman, M. Z., Xiao, M., Van Moer, K., Hasmim, M., Benoit, A., Bosseler, M., Viry, E., Arakelian, T., Berchem, G., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01846-x · Cited by 129 · see citing works
Fu, Z., Mowday, A. M., Smaill, J. B., Hermans, I. F., & Patterson, A. V. (2021) · Cells · doi:10.3390/cells10051006 · Cited by 133 · see citing works
Specialized immune responses in the peritoneal cavity and omentum
Liu, M., Silva-Sánchez, A., Randall, T. D., & Meza‐Perez, S. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.5mir0720-271rr · Cited by 132 · see citing works
Evolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma
Nie, M., Yao, K., Zhu, X., Chen, N., Xiao, N., Wang, Y., Peng, B., Yao, L., Li, P., Zhang, P., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26685-y · Cited by 126 · see citing works
The roles of PD-1/PD-L1 in the prognosis and immunotherapy of prostate cancer
Xu, Y., Song, G., Xie, S., Jiang, W., Chen, X., Chu, M., Hu, X., & Wang, Z. P. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.04.029 · Cited by 121 · see citing works
Hypoxia signaling in cancer: Implications for therapeutic interventions
Zhuang, Y., Liu, K., He, Q., Gu, X., Jiang, C., & Wu, J. (2023) · MedComm · doi:10.1002/mco2.203 · Cited by 119 · see citing works
Microenvironmental influences on T cell immunity in cancer and inflammation
Heintzman, D. R., Fisher, E. L., & Rathmell, J. C. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00833-2 · Cited by 119 · see citing works
Boreel, D. F., Span, P. N., Heskamp, S., Adema, G. J., & Bussink, J. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3913 · Cited by 117 · see citing works
Current developments in nanotechnology for improved cancer treatment, focusing on tumor hypoxia
Phung, C. D., Tran, T. H., Pham, L. M., Nguyen, H. T., Jeong, J., Yong, C. S., & Kim, J. O. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.05.029 · Cited by 115 · see citing works
Salman, S., Meyers, D. J., Wicks, E. E., Lee, S. N., Datan, E., Thomas, A. M., Anders, N. M., Hwang, Y., Lyu, Y., Yang, Y., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci156774 · Cited by 111 · see citing works
“In mouse models, hypoxic zones within tumors were shown to lack T cells (37, 38).”
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 · see citing works
Brooks, J. M., de Menezes, A. N., Ibrahim, M., Archer, L., Lal, N., Bagnall, C. J., von Zeidler, S. V., Valentine, H. R., Spruce, R. J., Batis, N., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3314 · Cited by 109 · see citing works
Hypoxia in Solid Tumors: How Low Oxygenation Impacts the “Six Rs” of Radiotherapy
Rakotomalala, A., Escande, A., Furlan, A., Meignan, S., & Lartigau, E. F. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.742215 · Cited by 119 · see citing works
The Immune Microenvironment and Cancer MetastasisPreprint
El-Kenawi, A., Hänggi, K., & Ruffell, B. (2019) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a037424 · Cited by 111 · see citing works
Freeman, P., & Mielgo, A. (2020) · Cancers · doi:10.3390/cancers12092687 · Cited by 102 · see citing works
Integrated Multi-Omics Landscape of Liver Metastases
Yang, S., Qian, L., Li, Z., Li, Y., Bai, J., Zheng, B. J., Chen, K., Qiu, X., Cai, G., Wang, S., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.11.029 · Cited by 102 · see citing works
Sono/Photodynamic Nanomedicine‐Elicited Cancer Immunotherapy
Li, Y., Xie, J., Um, W., You, D. G., Kwon, S., Zhang, L., Zhu, J., & Park, J. H. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202008061 · Cited by 99 · see citing works
Immune Checkpoint Inhibitors in Prostate Cancer
Venkatachalam, S., McFarland, T. R., Agarwal, N., & Swami, U. (2021) · Cancers · doi:10.3390/cancers13092187 · Cited by 99 · see citing works
Alleviating hypoxia to improve cancer immunotherapy
Fan, P., Zhang, N., Candi, E., Agostini, M., Piacentini, M., Bernassola, F., Bove, P., Alessandro, M., Giuseppe, N., Valentina, R., et al. (2023) · Oncogene · doi:10.1038/s41388-023-02869-2 · Cited by 99 · see citing works
Zai, W., Kang, L., Dong, T., Wang, H., Yin, L., Gan, S., Lai, W., Ding, Y., Hu, Y., & Wu, J. (2021) · ACS Nano · doi:10.1021/acsnano.1c07621 · Cited by 97 · see citing works
Chambers, A. M., & Matosevic, S. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00060 · Cited by 95 · see citing works
Zalfa, C., & Paust, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.633205 · Cited by 78 · see citing works
Li, T., Liu, T., Zhu, W., Xie, S., Zhao, Z., Feng, B., Guo, H., & Yang, R. (2021) · Clinical Medicine Insights Oncology · doi:10.1177/11795549211035540 · Cited by 94 · see citing works
Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy
Hao, Z., Li, R., Wang, Y., Li, S., Hong, Z., & Han, Z. (2021) · Biomarker Research · doi:10.1186/s40364-021-00333-5 · Cited by 94 · see citing works
The tumor microenvironment and immune responses in prostate cancer patients
Kwon, J., Bryant, R. J., & Parkes, E. E. (2021) · Endocrine Related Cancer · doi:10.1530/erc-21-0149 · Cited by 93 · see citing works
Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies
Park, K., Veena, M. S., & Shin, D. S. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.830208 · Cited by 90 · see citing works
Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments
Feldman, L. A. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1384249 · Cited by 94 · see citing works
Hypoxia Reduction Sensitizes Refractory Cancers to Immunotherapy
Jayaprakash, P., Vignali, P., Delgoffe, G. M., & Curran, M. A. (2021) · Annual Review of Medicine · doi:10.1146/annurev-med-060619-022830 · Cited by 86 · see citing works
Self-citationMiar, A., Arnaiz, E., Bridges, E., Beedie, S., Cribbs, A. P., Downes, D. J., Beagrie, R., Rehwinkel, J., & Harris, A. L. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-2306 · Cited by 85 · see citing works
Liu, X., Ye, N., Liu, S., Guan, J., Deng, Q., Zhang, Z., Xiao, C., Ding, Z., Zhang, B., Chen, X., et al. (2021) · Advanced Science · doi:10.1002/advs.202100233 · Cited by 83 · see citing works
Integrating tumor hypoxic stress in novel and more adaptable strategies for cancer immunotherapy
Khouzam, R. A., Venkatesh, G. H., Zaarour, R. F., Chamseddine, A. N., Francis, A., Buart, S., Terry, S., & Chouaı̈b, S. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.01.003 · Cited by 83 · see citing works
Surmounting the obstacles that impede effective CAR T cell trafficking to solid tumors
Donnadieu, E., Dupré, L., Pinho, L. G., & Cotta-de-Almeida, V. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1mr0520-746r · Cited by 82 · see citing works
Khouzam, R. A., Zaarour, R. F., Brodaczewska, K. K., Azakir, B., Venkatesh, G. H., Thiery, J., Terry, S., & Chouaı̈b, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.828875 · Cited by 80 · see citing works
Tumor hypoxia unveiled: insights into microenvironment, detection tools and emerging therapies
Ciepła, J., & Smolarczyk, R. (2024) · Clinical and Experimental Medicine · doi:10.1007/s10238-024-01501-1 · Cited by 81 · see citing works
TLR9 activation cooperates with T cell checkpoint blockade to regress poorly immunogenic melanoma
Reilley, M. J., Morrow, B., Ager, C. R., Liu, A. J., Hong, D. S., & Curran, M. A. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0811-x · Cited by 78 · see citing works
Self-citationTherapeutic strategies to remodel immunologically cold tumors
Wang, M., Wang, S., Desai, J., Trapani, J. A., & Neeson, P. J. (2020) · Clinical & Translational Immunology · doi:10.1002/cti2.1226 · Cited by 78 · see citing works
Newly Developed Prodrugs and Prodrugs in Development; an Insight of the Recent Years
Najjar, A., Najjar, A., & Karaman, R. (2020) · Molecules · doi:10.3390/molecules25040884 · Cited by 74 · see citing works
Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy
Hatfield, S. M., & Sitkovsky, M. V. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137554 · Cited by 73 · see citing works
Wurster, S., Watowich, S. S., & Kontoyiannis, D. P. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1018202 · Cited by 73 · see citing works
The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy
Li, Y., Zhao, L., & Li, X.-F. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.636892 · Cited by 72 · see citing works
Guillebon, É. D., Dardenne, A., Saldmann, A., Séguier, S., Tran, T., Paolini, L., Lebbé, C., & Tartour, É. (2020) · International Journal of Cancer · doi:10.1002/ijc.32889 · Cited by 76 · see citing works
Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy
Zemek, R. M., Chin, W. L., Nowak, A. K., Millward, M., Lake, R., & Lesterhuis, W. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00223 · Cited by 73 · see citing works
Recent progress in nitric oxide-generating nanomedicine for cancer therapy
Li, Y., Yoon, B., Dey, A., Nguyen, V. Q., & Park, J. H. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.10.012 · Cited by 68 · see citing works
Petrylak, D. P., Ratta, R., Matsubara, N., Korbenfeld, E. P., Gafanov, R. A., Mourey, L., Todenhöfer, T., Gurney, H., Kramer, G., Bergman, A. M., et al. (2025) · Journal of Clinical Oncology · doi:10.1200/jco-24-01283 · Cited by 66 · see citing works
Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research
Saranyutanon, S., Deshmukh, S. K., Dasgupta, S., Pai, S. G., Singh, S., & Singh, A. P. (2020) · Cancers · doi:10.3390/cancers12092651 · Cited by 65 · see citing works
Hypoxia, a key factor in the immune microenvironment
Hu, J., Li, X., Yang, L., & Li, H. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113068 · Cited by 65 · see citing works
Intratumoral hypoxia and mechanisms of immune evasion mediated by hypoxia-inducible factors
Semenza, G. L. (2021) · Physiology · doi:10.1152/physiol.00034.2020 · Cited by 64 · see citing works
- Authors
- Jayaprakash, P., Ai, M., Liu, A., Budhani, P., Bartkowiak, T., Sheng, J., Ager, C., Nicholas, C., Jaiswal, A. R., Sun, Y., Shah, K., Balasubramanyam, S., Li, N., Wang, G., Ning, J., Zal, A., Zal, T., & Curran, M. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Curran, Michael A.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-10-15
- Volume
- 128
- Issue
- 11
- Pages
- 5137-5149
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6205399
- OpenAlex
- W2890762462
- Cited by
- 399
- References
- 42
- Citations by year
- 2026: 36 · 2025: 42 · 2024: 47 · 2023: 54 · 2022: 75 · 2021: 72 · 2020: 48 · 2019: 22 · 2018: 3
- FWCI
- 13.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Prevention Research Institute of Texas (RP170399)
- Cancer Research Institute (CLIP-Curran)
- National Cancer Institute (P50 CA140388)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- prostate cancer, tumor hypoxia, TH-302, hypoxia-activated prodrug, CTLA-4 blockade, anti-PD-1 therapy, immune checkpoint blockade, T cell infiltration, cold tumors, myeloid-derived suppressor cells, immunotherapy resistance, PTEN, SMAD4, neuroendocrine prostate cancer
- MeSH terms
- Adenocarcinoma, Animals, Immunotherapy, Male, Neoplasm Proteins, Neoplasms, Experimental, Nitroimidazoles, Phosphoramide Mustards, Prostatic Neoplasms, T-Lymphocytes, Cell Hypoxia, Mice, Knockout, Cell Line, Tumor, 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
