Rise of PD-L1 expression during metastasis of colorectal cancer: Implications for immunotherapy
Abstract
OBJECTIVE: Programmed death‐ligand 1 (PD‐L1) expression in colorectal cancer (CRC) was implicated in predicting anti‐PD‐1/PD‐L1 therapy efficacy. However, therapeutic response has also been found in patients without PD‐L1 expression in the primary tumor. In the present study, we aimed to clarify the prevalence of PD‐L1 in primary and metastatic CRC. METHODS: The expression of PD‐L1 was determined by immunohistochemistry in matched primary and metastatic CRC. RESULTS: PD‐L1 expression was significantly more prevalent in metastatic CRCs than in primary tumors, and the expression of PD‐L1 in primary CRC may not represent the tumors that spread to distant organs. Positive expression of PD‐L1 was found in 81.8% of metastatic CRC, being significantly more prevalent than in primary CRC (40.9%; P = 0.012, Fisher’s exact test). While comparing the primary and metastatic lesions of the same patients, we found that PD‐L1 expression frequently increased during the metastatic process. However, PD‐L1 expression was rarely decreased in metastatic lesions. Intratumoral heterogeneity expression of PD‐L1 was found in both metastatic CRC (22.2%) and primary CRCs (33.3%). PD‐L1 was prevalently expressed in metastatic CRC, and increased PD‐L1 expression was frequently found in metastatic CRC as compared to primary tumors. CONCLUSION: PD‐L1 expression in metastatic CRC should be considered as an independent factor while evaluating the suitability of patients for immunotherapy.
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PD-L1 expression has been linked to poor clinical outcomes and is more common in metastatic colorectal cancer.
“Overall, PD-L1 expression has been linked to poor clinical outcomes, being more common in mCRC [109].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [109]
Cites
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628 · see citing works
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500596 · Cited by 9,377 · see citing works
Self-citationImmune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy
Topalian, S. L., Drake, C. G., & Pardoll, D. M. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.001 · Cited by 4,229 · see citing works
Colorectal cancer statistics, 2017
Siegel, R. L., Miller, K. D., Fedewa, S. A., Ahnen, D. J., Meester, R. G. S., Barzi, A., & Jemal, A. (2017) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21395 · Cited by 3,807 · see citing works
Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy
Topalian, S. L., Taube, J. M., Anders, R. A., & Pardoll, D. M. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.36 · Cited by 2,733 · see citing works
Taube, J. M., Klein, A., Brahmer, J. R., Xu, H., Pan, X., Kim, J. H., Chen, L., Pardoll, D. M., Topalian, S. L., & Anders, R. A. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-3271 · Cited by 2,324 · see citing works
Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity
Li, C., Lim, S., Xia, W., Lee, H., Chan, L.-C., Kuo, C., Khoo, K., Chang, S.-S., Cha, J., Kim, T., et al. (2016) · Nature Communications · doi:10.1038/ncomms12632 · Cited by 1,100 · see citing works
Self-citationDiet, microorganisms and their metabolites, and colon cancer
O'Keefe, S. J. D. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.165 · Cited by 1,100 · see citing works
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance
Hugo, W., Shi, H., Sun, L., Piva, M., Song, C., Kong, X., Moriceau, G., Hong, A., Dahlman, K. B., Johnson, D. B., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.061 · Cited by 596 · see citing works
Therapy-induced tumour secretomes promote resistance and tumour progression
Obenauf, A. C., Zou, Y., Ji, A. L., Vanharanta, S., Shu, W., Shi, H., Kong, X., Bosenberg, M., Wiesner, T., Rosen, N. X., et al. (2015) · Nature · doi:10.1038/nature14336 · Cited by 485 · see citing works
Callea, M., Albiges, L. K., Gupta, M., Cheng, S., Genega, E. M., Fay, A. P., Song, J., Carvo, I., Bhatt, R. S., Atkins, M. B., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0043 · Cited by 459 · see citing works
Rosenbaum, M. W., Bledsoe, J. R., Morales‐Oyarvide, V., Huynh, T. G., & Mino-Kenudson, M. A. (2016) · Modern Pathology · doi:10.1038/modpathol.2016.95 · Cited by 289 · see citing works
Wang, Z., Zhang, C., Liu, X., Wang, Z., Sun, L., Li, G., Liang, J., Hu, H., Liu, Y., Zhang, W., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1196310 · Cited by 191 · see citing works
PD-L1 Expression and Intratumoral Heterogeneity Across Breast Cancer Subtypes and Stages
Dill, E. A., Gru, A. A., Atkins, K. A., Friedman, L. A., Moore, M. E., Bullock, T. N. J., Cross, J. V., Dillon, P. M., & Mills, A. M. (2017) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000780 · Cited by 158 · see citing works
Heterogeneity of Programmed Cell Death Ligand 1 Expression in Multifocal Lung Cancer
Mansfield, A. S., Murphy, S. J., Peikert, T., Yi, E. S., Vasmatzis, G., Wigle, D. A., & Aubry, M. C. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2246 · Cited by 134 · see citing works
Inoue, H., Park, J., Kiyotani, K., Zewde, M. G., Miyashita, A., Jinnin, M., Kiniwa, Y., Okuyama, R., Tanaka, R., Fujisawa, Y., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1204507 · Cited by 134 · see citing works
Obeid, J. M., Erdag, G., Smolkin, M. E., Deacon, D. H., Patterson, J. W., Chen, L., Bullock, T. N. J., & Slingluff, C. L. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1235107 · Cited by 129 · see citing works
Immunotherapy for colorectal cancer: where are we heading?
Basile, D., Garattini, S. K., Bonotto, M., Ongaro, E., Casagrande, M., Cattaneo, M., Fanotto, V., Carlo, E. D., Loupakis, F., Urbano, F., et al. (2017) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2017.1315405 · Cited by 99 · see citing works
Inaguma, S., Lasota, J. P., Wang, Z., Felisiak-Gołąbek, A., Ikeda, H., & Miettinen, M. (2016) · Modern Pathology · doi:10.1038/modpathol.2016.185 · Cited by 94 · see citing works
Wang, H., Yao, H., Li, C., Liang, L., Zhang, Y., Shi, H., Zhou, C., Chen, Y., Fang, J., & Xu, J. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1327494 · Cited by 88 · see citing works
Self-citationWang, H., Liang, L., Fang, J.-Y., & Xu, J. (2015) · Oncogene · doi:10.1038/onc.2015.304 · Cited by 85 · see citing works
Self-citationAi, L., Tian, H., Chen, Z., Chen, H., Xu, J., & Fang, J. (2017) · Oncotarget · doi:10.18632/oncotarget.14488 · Cited by 78 · see citing works
Self-citationTargeting the PD-1 pathway: a new hope for gastrointestinal cancers
Bi̇lgi̇n, B., Şendur, M. A. N., Akıncı, M. B., Dede, D. Ş., & Yalçın, B. (2017) · Current Medical Research and Opinion · doi:10.1080/03007995.2017.1279132 · Cited by 75 · see citing works
ArhGAP30 promotes p53 acetylation and function in colorectal cancer
Wang, J., Qian, J., Hu, Y., Kong, X., Chen, H., Shi, Q., Jiang, L., Wu, C., Zou, W., Chen, Y., et al. (2014) · Nature Communications · doi:10.1038/ncomms5735 · Cited by 69 · see citing works
Self-citationAnti program death-1/anti program death-ligand 1 in digestive cancers
Guillebon, É. D. (2015) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v7.i8.95 · Cited by 53 · see citing works
An Expanding Role for Immunotherapy in Colorectal Cancer
Bever, K. M., & Le, D. T. (2017) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2017.0037 · Cited by 49 · see citing works
Methylation levels of LINE-1 in primary lesion and matched metastatic lesions of colorectal cancer
Murata, A., Baba, Y., Watanabe, M., Shigaki, H., Miyake, K., Ishimoto, T., Iwatsuki, M., Iwagami, S., Sakamoto, Y., Miyamoto, Y., et al. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.289 · Cited by 47 · see citing works
Mehta, K. R., Nakao, K., Zuraek, M. B., Ruan, D. T., Bergsland, E. K., Venook, A. P., Moore, D. H., Tokuyasu, T. A., Jain, A. N., Warren, R. S., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1418 · Cited by 41 · see citing works
Liu, Q. Q., Wang, H. L., Chen, K., Wang, S. B., Xu, Y., Ye, Q., & Sun, Y. W. (2015) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12314 · Cited by 40 · see citing works
Self-citationZhang, Y., Hu, Y., Wang, J.-L., Yao, H., Wang, H., Liang, L., Li, C., Shi, H., Chen, Y., Fang, J.-Y., et al. (2017) · Oncogene · doi:10.1038/onc.2017.152 · Cited by 32 · see citing works
Self-citationPatients’ knowledge and fear of colorectal cancer risk in inflammatory bowel disease
Lopez, A., Collet-Fenêtrier, B., Belle, A., & Peyrin‐Biroulet, L. (2016) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12356 · Cited by 15 · see citing works
Kessels, K., Eisinger, J. D., Letteboer, T. G. W., Offerhaus, G. J. A., Siersema, P. D., & Moons, L. M. G. (2017) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12491 · Cited by 13 · see citing works
Qi, Q. Q., Chen, F. X., Zhao, D. Y., Li, L. X., Wang, P., Li, Y. Q., & Zuo, X. L. (2016) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12374 · Cited by 12 · see citing works
Chinese consensus on the prevention of colorectal cancer (2016, S hanghai)
Fang, J., Yong Quan, S. H. I., Chen, Y., Li, J., & Sheng, J. Q. (2017) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12450 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Comprehensive review of targeted therapy for colorectal cancer
Xie, Y.-H., Chen, Y.-X., & Fang, J.-Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0116-z · Cited by 1,687 · see citing works
Self-citationPD-1/PD-L1 pathway: current researches in cancer.
Han, Y., Liu, D., & Li, L. (2020) · PubMed Central · Cited by 1,602 · see citing works
PD‐1/PD‐L1 immune checkpoint: Potential target for cancer therapy
Dermani, F. K., Samadi, P., Rahmani, G., Kohlan, A. K., & Najafi, R. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27172 · Cited by 509 · see citing works
“H. B. Wang et al. (2017) analyzed the expression of PD‐L1 in a great series of colorectal samples in tumor‐infiltrating immune cells as well as TCs.”
BackgroundPD-1/ PD-L1 blockade as a novel treatment for colorectal cancer
Yaghoubi, N., Soltani, A., Ghazvini, K., Hassanian, S. M., & Hashemy, S. I. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.11.105 · Cited by 303 · see citing works
Regulation of PD-L1: Emerging Routes for Targeting Tumor Immune Evasion
Wang, Y., Wang, H., Yao, H., Li, C., Fang, J., & Xu, J. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00536 · Cited by 209 · see citing works
Self-citationChen, J., Lin, Z., Liu, L., Zhang, R., Geng, Y., Fan, M.-H., Zhu, W., Lü, M., Lu, L., Jia, H., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00784-0 · Cited by 193 · see citing works
Emerging trends in colorectal cancer: Dysregulated signaling pathways (Review)
Ahmad, R., Singh, J. K., Wunnava, A., Al-Obeed, O. A., Abdulla, M., & Srivastava, S. K. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4847 · Cited by 254 · see citing works
Cancer Cell-Intrinsic PD-1 and Implications in Combinatorial Immunotherapy
Yao, H., Wang, H., Li, C., Fang, J., & Xu, J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01774 · Cited by 154 · see citing works
Self-citationLequeux, A., Noman, M. Z., Xiao, M., Sauvage, D., Van Moer, K., Viry, E., Bocci, I., Hasmim, M., Bosseler, M., Berchem, G., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.021 · Cited by 117 · see citing works
Molecular imaging biomarkers for immune checkpoint inhibitor therapy
van de Donk, P. P., de Ruijter, L. K., Hooge, M. N. L., Brouwers, A. H., van der Wekken, A. J., Oosting, S. F., Fehrmann, R. S. N., de Groot, D. J. A., & de Vries, E. G. E. (2020) · Theranostics · doi:10.7150/thno.38339 · Cited by 106 · see citing works
“Furthermore, tumor biopsies do not take into account the spatial heterogeneity of PD-L1 target expression, which can highly differ within and across metastases within one patient (15, 40-47).”
BackgroundSoler, A., Cayrefourcq, L., Mazard, T., Babayan, A., Lamy, P., Assou, S., Assénat, E., Pantel, K., & Alix‐Panabières, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-34365-z · Cited by 92 · see citing works
Mechanisms of Immunosuppression in Colorectal Cancer
Zhang, Y., Rajput, A., Jin, N. Y., & Wang, J. (2020) · Cancers · doi:10.3390/cancers12123850 · Cited by 81 · see citing works
“Interestingly, PD-L1 expression is more prevalent in metastatic CRCs than in primary tumors [45].”
BackgroundSelf-citationAnti-PD-1/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations
Chen, X., Chen, L., Peng, X., Deng, L., Wang, Y., Li, J.-J., Guo, D., & Niu, X. (2023) · Translational Oncology · doi:10.1016/j.tranon.2023.101851 · Cited by 80 · see citing works
“Immunohisto-chemical studies have revealed that metastatic CRCs have a higher incidence of PD-L1 expression than primary tumors [27].”
BackgroundExtracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives
Raimondo, S., Pucci, M., Alessandro, R., & Fontana, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072286 · Cited by 76 · see citing works
Kang, D. Y., Sp, N., Lee, J., & Jang, K. (2021) · Biomedicines · doi:10.3390/biomedicines9030297 · Cited by 75 · see citing works
“Studies have shown that PD-L1 actively participates in tumor metastasis processes other than immune escape regulation [28].”
Durinikova, E., Kozovská, Z., Poturnajova, M., Plavá, J., Čierna, Z., Bábelová, A., Bohovic, R., Schmidtova, S., Tomáš, M., Kučerová, L., et al. (2018) · BMC Cancer · doi:10.1186/s12885-018-4758-y · Cited by 70 · see citing works
Mohan, N., Hosain, S. B., Zhao, J. W., Shen, Y., Luo, X. L., Jiang, J., Endo, Y., & Wu, W. J. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1624128 · Cited by 64 · see citing works
“Tissue microarray analysis from colorectal cancers reveal that PD-L1 is predominantly expressed in metastatic tumors compared with primary tumor suggesting that PD-L1 expression rises during metastatic spread of tumor.(35) Likewise, analysis of PD-L1 expression in lymph-node positive TNBC patients suggest that PD-L1 i…”
BackgroundBitar, S. A., El-Sabban, M. E., Doughan, S., & Abou-Kheir, W. G. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i9.1395 · Cited by 67 · see citing works
Manson, Q. F., Schrijver, W. A. M. E., ter Hoeve, N. D., Moelans, C. B., & van Diest, P. J. (2018) · Clinical & Experimental Metastasis · doi:10.1007/s10585-018-9950-6 · Cited by 63 · see citing works
Li, D., Zhang, T., Guo, Y., Bi, C., Liu, M., & Wang, G. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06888-z · Cited by 63 · see citing works
Xu, Y., Zhao, J., Gao, C., Ni, X., Wang, W., Hu, W., & Wu, C. (2021) · Cellular Signalling · doi:10.1016/j.cellsig.2021.110095 · Cited by 56 · see citing works
Cheung, C. C., Barnes, P. J., Bigras, G., Boerner, S. L., BUTANY, J. W., Calabrese, F., Couture, C., Deschênes, J., El-Zimaity, H. M. T., Fischer, G., et al. (2019) · Applied immunohistochemistry & molecular morphology · doi:10.1097/pai.0000000000000800 · Cited by 56 · see citing works
Self-citationRugamba, A., Kang, D. Y., Sp, N., Jo, E. S., Lee, J., Bae, S. W., & Jang, K. (2021) · Cells · doi:10.3390/cells10071632 · Cited by 56 · see citing works
“A member of the Janus kinase family, JAK2 is involved in different cell signaling reactions [49], and this interaction with other proteins, such as STAT and PI3K, may cause cell death or tumor formation [50,51], mediate MMP proteins [33], and enhance PD-L1 regulation, which has been proven to have a role in tumor meta…”
BackgroundB7-H3 immune checkpoint expression is a poor prognostic factor in colorectal carcinoma
Lu, Z., Zhao, Z., Cheng, P., Huang, F., Guan, X., Zhang, M., Chen, H., Liu, Z., Jiang, Z., Zheng, Z., et al. (2020) · Modern Pathology · doi:10.1038/s41379-020-0587-z · Cited by 49 · see citing works
“Moreover, many studies showed that immune checkpoints, mainly PD-L1, were more commonly expressed in metastases than primary sites, including in CRC patients [49, 50].”
BackgroundMetastatic Colonization: Escaping Immune Surveillance
Schaller, J., & Agudo, J. (2020) · Cancers · doi:10.3390/cancers12113385 · Cited by 50 · see citing works
“Similarly, expression of PD-L1 is increased in metastases compared to primary lesions in colorectal cancer [67].”
BackgroundKoustas, E., Sarantis, P., Kyriakopoulou, G., Papavassiliou, A. G., & Karamouzis, M. V. (2019) · Cancers · doi:10.3390/cancers11040533 · Cited by 49 · see citing works
“have shown that metastatic colorectal cancer (mCRC) has higher levels of PD-L1 [121].”
BackgroundHigh degree of heterogeneity of PD-L1 and PD-1 from primary to metastatic endometrial cancer
Engerud, H., Berg, H. F., Myrvold, M., Halle, M. K., Bjørge, L., Haldorsen, I. S., Høivik, E. A., Trovik, J., & Krakstad, C. (2020) · Gynecologic Oncology · doi:10.1016/j.ygyno.2020.01.020 · Cited by 49 · see citing works
Sp, N., Kang, D. Y., Lee, J., & Jang, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189843 · Cited by 46 · see citing works
“This function has been proven to have a role in tumor metastasis and immune escape [43].”
BackgroundPolydatin Exerts an Antitumor Effect Through Regulating the miR-382/PD-L1 Axis in Colorectal Cancer
Jin, Y., Zhan, X., Zhang, B., Chen, Y., Liu, C., & Yu, L. (2019) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2019.2999 · Cited by 45 · see citing works
“36,37 41–43 Previous studies demonstrated that PD-L1 expression level was associated with prognosis of CRC patients.”
Self-citationHe, W., Hu, W.-M., Wang, F., Rong, Y.-M., Yang, L., Xie, Q.-K., Yang, Y., Jiang, C., Qiu, H., Lu, J.-B., et al. (2019) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2019.7308 · Cited by 44 · see citing works
Wei, X., Luo, X., Sheng, H., Wang, Y., Chen, D., Li, J.-N., Wang, F., & Xu, R. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02636-x · Cited by 43 · see citing works
“on 22 patients with CRC with metastasis whose metastatic lesion had higher PD-L1 expression than their primary tumor [28].”
Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy
Nikolouzakis, T. K., Chrysos, E., Docea, A. O., Fragkiadaki, P., Souglakos, J., Tsiaoussis, J., & Tsatsakis, A. (2024) · Cancers · doi:10.3390/cancers16111995 · Cited by 37 · see citing works
“Overall, PD-L1 expression has been linked to poor clinical outcomes, being more common in mCRC [109].”
BackgroundManzi, J. L. L., Hoff, C. O., Ferreira, R., Pimentel, A., Datta, J., Livingstone, A. S., Vianna, R., & Abreu, P. (2023) · Cancers · doi:10.3390/cancers15113023 · Cited by 40 · see citing works
Li, C., Chi, H., Deng, S., Xu, K., Wang, H., Yao, H., Wang, Y., Chen, D., Guo, X., Fang, J., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002443 · Cited by 37 · see citing works
Self-citationPredictors of response to immunotherapy in colorectal cancer
González‐Montero, J., Rojas, C. I., & Burotto, M. (2024) · The Oncologist · doi:10.1093/oncolo/oyae152 · Cited by 34 · see citing works
“28 Third, the methodology used for PD-L1 assessment affects its reliability.”
MethodPharmacogenomics, biomarker network, and allele frequencies in colorectal cancer
López‐Cortés, A., Paz‐y‐Miño, C., Guerrero, S. X., Jaramillo-Koupermann, G., Cáceres, Á. L., Intriago-Baldeón, D. P., García-Cárdenas, J. M., Guevara‐Ramírez, P., Armendáriz‐Castillo, I., Leone, P., et al. (2019) · The Pharmacogenomics Journal · doi:10.1038/s41397-019-0102-4 · Cited by 29 · see citing works
Vuletić, A. M., Martinović, K. M., Miletić, N. T., Zoidakis, J., Castellvı́-Bel, S., & Cavic, M. R. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.750022 · Cited by 26 · see citing works
Dostarlimab an Inhibitor of PD-1/PD-L1: A New Paradigm for the Treatment of Cancer
Alkholifi, F. K., & Alsaffar, R. M. (2022) · Medicina · doi:10.3390/medicina58111572 · Cited by 28 · see citing works
“The expression of PD-L1 in metastatic CRC should be taken into account separately for determining patient eligibility for immunotherapy [111].”
BackgroundUnveiling the immune symphony: decoding colorectal cancer metastasis through immune interactions
He, R., Huang, S., Lu, J., Su, L., Gao, X., & Chi, H. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1362709 · Cited by 29 · see citing works
“Research indicates that PD-L1 levels are higher in lung (45) and liver metastases (46) of colorectal cancer (CRC) than in primary tumors.”
BackgroundPang, S.-W., Awi, N. J., Armon, S., Lim, W. W.-D., Low, J. S.-H., Peh, K.-B., Peh, S., & Teow, S. (2019) · Diagnostics · doi:10.3390/diagnostics10010009 · Cited by 26 · see citing works
“It is speculated that these large variations could be attributed to the difference in immunohistochemistry staining methods and scoring criteria due to the spatial and temporal heterogeneity of PD-L1 expression in mCRC patients [71].”
BackgroundExpanding the Potential of Circular RNA (CircRNA) Vaccines: A Promising Therapeutic Approach
Bu, T., Yang, W., Zhao, J., Gao, Y., Li, F., & Yang, R. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26010379 · Cited by 30 · see citing works
Nong, K., Zhang, D., Chen, C., Yang, Y., Yong, Y., Liu, S., & Cai, H. (2019) · Oncology Letters · doi:10.3892/ol.2019.11234 · Cited by 26 · see citing works
“In cancer, high PD-L1 levels are associated with tumor progression and a poor prognosis (16).”
BackgroundAnticipating metastasis through electrochemical immunosensing of tumor hypoxia biomarkers
Martín, C. M., Gamella, M., Pedrero, M., Montero‐Calle, A., Pérez‐Ginés, V., Camps, J., Arenas, M., Barderas, R., Pingarrón, J. M., & Campuzano, S. (2021) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-021-03240-8 · Cited by 26 · see citing works
Jiang, H., Zhang, R., Jiang, H., Zhang, M., Guo, W., Zhang, J., Zhou, X., Pan, W., Zhao, S., & Li, P. (2020) · Journal of Cancer · doi:10.7150/jca.38689 · Cited by 24 · see citing works
Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer
Vuletić, A. M., Martinović, K. M., & Spasić, J. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics16010054 · Cited by 24 · see citing works
“Therapeutic blockade of PD-1 and its ligand with anti-PD-1 and anti-PD-L1 antibodies has shown a considerable clinical benefit in some metastatic CRCs [232,235].”
BackgroundExpression of PD-L1 in primary breast carcinoma and lymph node metastases
Alves, A. M. D. S., Paredes, J., & Schmitt, F. C. (2019) · Surgical and Experimental Pathology · doi:10.1186/s42047-019-0033-z · Cited by 21 · see citing works
Forces at play: exploring factors affecting the cancer metastasis
Riaz, F., Zhang, J., & Pan, F. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1274474 · Cited by 20 · see citing works
Soltani, M., Abbaszadeh, M., Fouladseresht, H., Sullman, M. J. M., & Eskandari, N. (2025) · Clinical and Experimental Medicine · doi:10.1007/s10238-025-01641-y · Cited by 18 · see citing works
“Recent investigations have revealed that PD-L1 expression tends to be more prevalent in observed in metastatic sites, like those found in liver and lung, compared to primary tumours [78, 79].”
Nanomaterial Manipulation of Immune Microenvironment in the Diseased Liver
Hu, M., & Huang, L. (2018) · Advanced Functional Materials · doi:10.1002/adfm.201805760 · Cited by 17 · see citing works
The role of the immunoescape in colorectal cancer liver metastasis
Takasu, C., Yamashita, S., Morine, Y., Yoshikawa, K., Tokunaga, T., Nishi, M., Kashihara, H., Yoshimoto, T., & Shimada, M. (2021) · PLoS ONE · doi:10.1371/journal.pone.0259940 · Cited by 15 · see citing works
“Furthermore, PD-L1 expression is higher in lung [8] and liver [13] metastases of patients with CRC compared with the cognate primary tumors.”
BackgroundThe clinical significance of PD‑L1 in colorectal cancer (Review)
Ntomi, V., Foukas, P. G., Papaconstantinou, D., Antonopoulou, I., Pikoulis, A., Panagiotides, I., Pikoulis, E. A., & Syrigos, K. (2021) · Oncology Reports · doi:10.3892/or.2021.8043 · Cited by 14 · see citing works
Möller, K., Blessin, N. C., Höflmayer, D., Büscheck, F., Luebke, A. M., Kluth, M., Hube‐Magg, C., Zalewski, K., Hinsch, A., Neipp, M., et al. (2021) · Acta Oncologica · doi:10.1080/0284186x.2021.1933585 · Cited by 14 · see citing works
Yang, L., Yang, X., He, W., Liu, S., Jiang, C., xie, K., Peng, K., You, Y., Zhang, B., & Xia, L. (2018) · Aging · doi:10.18632/aging.101700 · Cited by 14 · see citing works
“Despite their large numbers, neither clinical trials nor germinate immunotherapy-based treatments have shown significant improvements in patients with metastases [31, 32].”
BackgroundLiu, S., Zhang, Y., Lin, Y., Wang, P., & Pan, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.981527 · Cited by 13 · see citing works
Self-citationXin, H., Zhou, C., Wang, G., Liu, Y., Zhang, J., Liu, Y., Li, B., Zhang, J., Su, M., Li, Z., et al. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e13048 · Cited by 13 · see citing works
“Previous studies have reported that PD-L1 expression is enhanced in recurrent and metastatic tumours during colorectal cancer progression or metastasis [32].”
ResultHuemer, F., Klieser, E., Neureiter, D., Schlintl, V., Rinnerthaler, G., Pagès, F., Kirilovsky, A., Sissy, C. E., Iglseder, W., Singhartinger, F. X., et al. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9092775 · Cited by 13 · see citing works
“Given the known heterogeneity of PD-L1 expression within tumors [29], we cannot exclude bias resulting from the analysis of the initial diagnostic biopsy, and comparison with PD-L1 expression in the surgical resectate, since it only represents a small portion of the tumor.”
Retracted: LINC00657 activates PD‐L1 to promote osteosarcoma metastasis via miR‐106a
Zhang, J., Chou, X., Zhuang, M., Zhu, C., Hu, Y., Cheng, D., & Liu, Z. (2020) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29574 · Cited by 12 · see citing works
“Programmed death ligand‐1 ([PD‐L1], also known as CD274 or B7‐H1), is identified as a brake for T‐cell receptor‐mediated immune response.(19) The two biological molecules PDL‐1 and its receptor PD‐1 have been considered most promising targets for cancers.”
BackgroundRetractedEsch, J. S. A., Windmöller, B. A., Hanewinkel, J., Storm, J., Förster, C., Wilkens, L., Krüger, M., Kaltschmidt, B., & Kaltschmidt, C. (2020) · Cancers · doi:10.3390/cancers12092582 · Cited by 12 · see citing works
“Further, immune checkpoint ligand PDL1 is upregulated in EMT-activated human breast cancer cells [92] and was shown to be more highly expressed in metastatic CRC than in primary CRC [93], suggesting its correlation with stem cell characteristics.”
BackgroundImmunohistochemistry as predictive and prognostic markers for gastrointestinal malignancies
Rosenbaum, M. W., & González, R. S. (2021) · Seminars in Diagnostic Pathology · doi:10.1053/j.semdp.2021.10.003 · Cited by 11 · see citing works
Lee, C. C., Soon, Y. Y., Lum, H. Y. J., Tan, C. L., & Tey, J. C. S. (2020) · Acta Oncologica · doi:10.1080/0284186x.2020.1741678 · Cited by 11 · see citing works
Unson, S., Chang, T., Yang, Y., Wang, S., Huang, C., Crawford, D. R., Huang, H., Li, Z., Lin, H., Whang‐Peng, J., et al. (2022) · Marine Drugs · doi:10.3390/md20080482 · Cited by 11 · see citing works
“PD-L1 expression more often occurs in metastatic CRC, and its expression in primary CRC might not indicate that cancer cells have spread to distant locations in the body [10].”
BackgroundCancer invasion and metastasis: Insights from murine pubertal mammary gland morphogenesis
Githaka, J. M., Pirayeshfard, L., & Goping, I. S. (2023) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2023.130375 · Cited by 11 · see citing works
Molecular Subtypes, microRNAs and Immunotherapy Response in Metastatic Colorectal Cancer
Gherman, A., Bolunduț, D., Ecea, R., Bălăcescu, L., Curcean, S., Dina, C., Bălăcescu, O., & Cainap, C. I. (2024) · Medicina · doi:10.3390/medicina60030397 · Cited by 10 · see citing works
“In a recent study, PD-L1 expression was more prevalent in liver and lung metastatic foci compared to the primary tumor [74].”
BackgroundHydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux
Spangenberg, S. H., Palermo, A., Gazaniga, N. R., Martínez‐Peña, F., Guijas, C., Chin, E. N., Rinschen, M. M., Sander, P. N., Webb, B., Pereira, L. E., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.016 · Cited by 9 · see citing works
Immunotherapy against colorectal cancer via delivery of anti-PD-L1 nanobody mRNA
Chu, W., Ma, L., Hew, B. E., Sugawara, A., Wengrill, R., Guarary, A., Irei, J. S., Chan, O. T. M., Wang, J., Muramtsu, H., et al. (2025) · eGastroenterology · doi:10.1136/egastro-2024-100106 · Cited by 7 · see citing works
Spatiotemporal Changes in Checkpoint Molecule Expression
Li, W., Qie, J., Zhang, Y., & Chang, J. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-3266-5_8 · Cited by 7 · see citing works
Self-citationPark, A., Kim, J. H., Lee, S. E., Kim, H., Kim, H., Lee, H., & Han, W. (2025) · International Journal of Oncology · doi:10.3892/ijo.2025.5760 · Cited by 5 · see citing works
“PD‑L1 expression is more frequently observed in metastatic tumors, where it correlates with poor prognosis and serves as a biomarker for immunotherapy eligibility (49).”
Hemida, N., El‐Gamil, D. S., ElHady, A. K., Lin, K.-C., Chang, Y.-H., Hilscher, S., Schutkowski, M., Ibrahim, H. S., Hamed, M. M., Chen, S., et al. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108454 · Cited by 5 · see citing works
Therapeutic Potential of Mitotic Kinases’ Inhibitors in Cancers of the Gastrointestinal System
Javed, A., Malagraba, G., Yarmohammadi, M., Perelló-Reus, C. M., Barceló, C., & Rubio‐Tomás, T. (2022) · Future Pharmacology · doi:10.3390/futurepharmacol2030015 · Cited by 5 · see citing works
Damato, A., Rotolo, M., Caputo, F., Borghi, E., Iachetta, F., & Pinto, C. (2022) · Life · doi:10.3390/life12081137 · Cited by 5 · see citing works
“[94] showed that PD-L1 expression was correlated with lymphatic invasion and tumor diameter but negatively with differentiation and vascular invasion.”
BackgroundKarjula, T., Elomaa, H., Niskakangas, A., Mustonen, O., Puro, I., Kuopio, T., Ahtiainen, M., Mecklin, J., Seppälä, T. T., Wirta, E., et al. (2022) · Cancers · doi:10.3390/cancers15010206 · Cited by 5 · see citing works
“Taken together, it appears that whereas high tumour cell PD-L1 expression in primary tumours predicts poor survival at least in early stage CRC, it has an opposite effect in CRC metastases, despite the observation that PD-L1 expression elevates in metastases in comparison to the primary tumour [32].”
BackgroundBaicalein Enhances Radiosensitivity in Colorectal Cancer via JAK2 / STAT3 Pathway Inhibition
Yu, Q., Tang, R., Mo, W., Zhao, L., & Li, L.-D. (2024) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14611 · Cited by 5 · see citing works
“Previous studies have shown higher PD-L1 expression in metastatic CRC compared to primary tumors (Wang, Yao, et al. 2017), and PD-1/PD-L1 blockade has been proposed as a promising therapy for CRC (Yaghoubi et al. 2019).”
Chen, S., Zhang, L., Wang, K., Huo, J., Zhang, S., & Zhang, X. (2023) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2023/5521544 · Cited by 4 · see citing works
“Previous studies showed that PD-L1 expression was higher in metastatic CRC than in primary tumors [37].”
ResultPD-L1 Expression in Paired Samples of Rectal Cancer
Coussement, M., Fazio, R., Audisio, A., Khoury, R. E., Abbassi, F.-Z., Assaf, I., Conti, C., Gallio, C., Benhima, N., Bregni, G., et al. (2024) · Cancers · doi:10.3390/cancers16142606 · Cited by 3 · see citing works
“Selected studies reporting the expression of PD-L1 in locally advanced rectal cancers.”
BackgroundQuinidine dosage in children using population estimates.
Burckart, G. J., & Marı́n-Garcı́a, J. (1986) · PubMed · Cited by 3 · see citing works
Франк, Г. А., Кузнецова, О. А., Эдуардовна, З. Л., Andreeva, Y. Y., & Moskvina, L. V. (2019) · Russian Journal of Archive of Pathology · doi:10.17116/patol2019810515 · Cited by 3 · see citing works
“[9] при исследовании колоректального рака.”
Suwal, N., Thapa, R., Bashyal, S., Sugandhi, V. V., Subedi, S., Panth, N., Amorim, N. M. L., Choi, J. P., Gupta, M., Idrees, S., et al. (2025) · Food Bioscience · doi:10.1016/j.fbio.2025.106887 · Cited by 2 · see citing works
He, J. N., Gao, Y., Sun, Z. S., Li, Y., Wang, J., Zhang, L., & Liu, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1686071 · Cited by 2 · see citing works
Expresion paterns of various PDCD1 and PDL1 isoforms in prostate tumors
Gerashchenko, G. V., Kononenko, O. A., Bondarenko, Y. M., Stakhovsky, E. O., Tkachuk, Z. Y., Tukalo, M. A., & Kashuba, V. I. (2022) · Biopolymers and Cell · doi:10.7124/bc.000a7c · Cited by 2 · see citing works
Tadachina, S., Shivalingaiah, S. D. C., & Shetty, M. (2024) · Iranian journal of pathology · doi:10.30699/ijp.2023.1988660.3054 · Cited by 2 · see citing works
“Checkpoint blockade drugs targeting PD-1 and its ligand, PD-L1, have had exceptional clinical results in various cancers (4).”
BackgroundExploring the potential biological function of GRK2 in colorectal cancer
Gao, M., Liang, X., Fan, M., Wu, Y., Dong, M., & Du, R. (2024) · Functional & Integrative Genomics · doi:10.1007/s10142-024-01322-1 · Cited by 1 · see citing works
Beaino, Z. E., Dupain, C., Marret, G., Paolettí, X., Fuhrmann, L., Martinat, C., Allory, Y., Halladjian, M., Bièche, I., Tourneau, C. L., et al. (2024) · The Journal of Pathology · doi:10.1002/path.6334 · Cited by 1 · see citing works
“This heterogeneity in PD-L1 expression was in line with the results of Wang et al in 22 patients with metastatic colorectal cancer whose metastatic lesion showed higher PD-L1 expression than the primary tumor [48].”
Fang, J., Jiang, O., Li, W., Lin, J., Fang, M., Li, Q., Zhao, W., Wang, K., Shi, H., Chen, Z., et al. (2025) · Drug Design Development and Therapy · doi:10.2147/dddt.s546663 · Cited by 1 · see citing works
Self-citationGrape, L. M., Hanke, B., Neyazi, B., Rashidi, A., Swiatek, V. M., Schaufler, A., Dumitru, C. A., Kahlert, U. D., Croner, R. S., Mawrin, C., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1816086 · Cited by 1 · see citing works
“These observations are consistent with previous studies reporting frequent discordance in PD-L1 expression between primary and metastatic CRC lesions, with a tendency toward higher expression in metastases (55, 56).”
Impact of cancer immunotherapies on oocyte health and ovarian function
Lewis, Y., Cao, Y., Higgins, J., Alesi, L. R., Winship, A., & Hutt, K. J. (2026) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2026.04.006 · Cited by 1 · see citing works
Zarbakhsh, A., Khalaji, A., Vahedi, A., Dolatkhah, R., & Gholami, N. (2024) · European Journal of Cancer Care · doi:10.1155/2024/5578953 · Cited by 1 · see citing works
Current drug therapy for colorectal cancer
Mohapatra, L., Tripathi, A. S., Alka, Mishra, D. K., Parida, S. K., Yasir, M., Maurya, R. K., & Prajapati, B. G. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13870-6.00014-3 · Cited by 1 · see citing works
Recent Advancements in the Inhibition of Metastasis of Colorectal Cancer Using Anticancer Compounds
Chhetri, D., Ilango, K., Palaniyandi, K., & Gnanasampanthapandian, D. (2024) · Springer eBooks · doi:10.1007/978-981-99-6263-1_48 · Cited by 1 · see citing works
kenari, S. N., Mohamadynejad, P., Moghanibashi, M., Bagheri, A., & Rouhi, L. (2025) · Biomarkers · doi:10.1080/1354750x.2024.2448508 · Cited by 1 · see citing works
“…(sreevalsan et al. 2020). in this regard, it has been shown that the expression of PD-l1 in metastatic cRcs is higher than in primary tumours (Wang et al. 2017) Mllt6 as a critical factor, also induces the interferon gamma (iFN-γ) signalling pathway by activating the transcriptional…”
Molecular biomarkers in current management of metastatic colorectal cancer
Tanasanvimon, S. (2018) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2018.38 · Cited by 1 · see citing works
“Also there are some evidenced of temporal and spatial heterogeneity of PD-L1 expression in mCRC([54,55]).”
BackgroundPrognostic value of tumor immune biomarkers in biopsies from patients with refractory solid cancers
Lambert, T., Pobel, C., Daage, L. C., Bigorgne, A., RaubyY, B., Aladro, N. S.-E., Ter-MinassianN, L., Kerisit, M., Marabelle, A., Besse, B., et al. (2022) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2022.100611
Recent Advancements in the Inhibition of Metastasis of Colorectal Cancer Using Anticancer Compounds
Chhetri, D., Ilango, K., Palaniyandi, K., & Gnanasampanthapandian, D. (2023) · Springer eBooks · doi:10.1007/978-981-99-2196-6_48-1
Ramadansyah, Alferraly, T. I., Chrestella, J., Delyuzar, & Laksmi, L. I. (2023) · International Journal of Research Publications · doi:10.47119/ijrp10013611120235637
Cancer signaling pathways: targets and treatment
Vishnusai, B., Sharma, R., Parihar, V. K., & Kumar, N. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95258-3.00006-0
Acute Hemorrhagic Rectal Ulcer in a Uremic Patient: A Case Report and Literature Review
Liu, D., Han, X., Li, M., Li, L., Huang, Y., & Song, J. (2025) · Hemodialysis International · doi:10.1111/hdi.13273
Wei, X.-L., Luo, X., Sheng, H., Wang, Y., Chen, D.-L., Li, J.-N., Wang, F.-H., & Xu, R.-H. (2020) · Figshare · doi:10.6084/m9.figshare.13468261
Impact du ciblage du domaine de liaison de HIF-1α avec HIF-1β sur le paysage immunitaire du mélanome
Lequeux, A. (2020) · theses.fr (ABES) · doi:10.70675/a29d12dbz79c1z4d37za978z2e2319131c82
Aguiari, G., Bianchi, N., & Franzese, O. (2026) · Cells · doi:10.3390/cells15121074
- Authors
- Wang, H. B., Yao, H., Li, C. S., Liang, L. X., Zhang, Y., Chen, Y. X., Fang, J., & Xu, J.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease Shanghai China
- Corresponding author
- Xu, Jie
- Venue
- Journal of Digestive Diseases
- Publisher
- Wiley
- Published
- 2017-10
- Volume
- 18
- Issue
- 10
- Pages
- 574-581
- ISSN
- 1751-2972 (ISSN-L)
- 1751-2980
- OpenAlex
- W2752071552
- Cited by
- 100
- References
- 34
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 16 · 2023: 10 · 2022: 8 · 2021: 13 · 2020: 17 · 2019: 11 · 2018: 11
- FWCI
- 4.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Digestive Diseases (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81572326, 81322036, 81272383, 81602518, 81502015, 81572303, 81530072, 81421001, 81320108024)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- PD-L1 expression, colorectal cancer, metastasis, primary tumor, intratumoral heterogeneity, PD-1/PD-L1 blockade, predictive biomarkers, tumor immune evasion
- MeSH terms
- Aged, Female, Humans, Immunohistochemistry, Immunotherapy, Male, Middle Aged, Neoplasm Metastasis, Colorectal Neoplasms, B7-H1 Antigen
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