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Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy
Open accessAbstract
Despite compelling rates of durable clinical responses to programmed cell death-1 (PD-1) blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8+ T cell response in tumor-bearing mice treated with anti-PD-1 but were not required for the infiltration of CD8+ T cells into tumors. The anti-PD-1-induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103+ dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands in murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non-responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.
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In the citing paper
“Additionally, CXCL10 has been shown to promote effector T cell generation and function56,57.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [57]
Experimental — accuracy not yet measuredIn the citing paper
“CXCL9/10/11 are ligands of the CXCR3 receptor involved in increased trafficking of CD8+CXCR3+ T cells to tumors (47,48,64).”
In the citing paper
“The relevance of the CXCL9/10/11-CXCR3 pathway for recruiting and triggering cytotoxic T cells is well known (47-50,64).”
In the citing paper
“Data suggest that CXCR3 is not essential for the early recruitment of CD8+ T cells into tumors (64).”
In the citing paper
“Their ligands are reported to function both as biomarkers and inducers of response to anti-PD-1 alone (64) or in combination with anti-CTLA-4 (47).”
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Citations
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BackgroundBarriers to immune cell infiltration in tumors
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Dietary Lactobacillus -Derived Exopolysaccharide Enhances Immune-Checkpoint Blockade Therapy
Kawanabe-Matsuda, H., Takeda, K., Nakamura, M., Makino, S., Karasaki, T., Kakimi, K., Nishimukai, M., Ohno, T., Omi, J., Kano, K., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0929 · Cited by 158
“It was recently reported that an IFN γ -dependent recruitment of CXCR3-expressing CD8 + T cells by CXCL9-producing CD103 + dendritic cells in the tumor was a critical event for anti–PD-1 mAb efficacy (8).”
KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance
Zavitsanou, A., Pillai, R., Yuan, H., Wu, W., Bartnicki, E., Karakousi, T. R., Rajalingam, S., Herrera, A. M., Karatza, A., Rashidfarrokhi, A., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113295 · Cited by 157
Liu, S., Iorgulescu, J. B., Li, S., Borji, M., Barrera, I., Shanmugam, V., Lyu, H., Morriss, J. W., Garcia, Z. N., Murray, E. M., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.09.002 · Cited by 148
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Trial watch: dendritic cell vaccination for cancer immunotherapy
Sprooten, J., Ceusters, J., Coosemans, A., Agostinis, P., Vleeschouwer, S. D., Zitvogel, L., Kroemer, G., Galluzzi, L., & Garg, A. D. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1638212 · Cited by 151
Bergamaschi, C., Pandit, H., Nagy, B. A., Stellas, D., Jensen, S. M., Bear, J., Cam, M. C., Valentin, A., Fox, B. A., Felber, B. K., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000599 · Cited by 141
Ozato, Y., Kojima, Y., Kobayashi, Y., Hisamatsu, Y., Toshima, T., Yonemura, Y., Masuda, T., Kagawa, K., Goto, Y., Utou, M., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2022.111929 · Cited by 144
Localization, tissue biology and T cell state — implications for cancer immunotherapy
Schenkel, J. M., & Pauken, K. E. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00884-8 · Cited by 144
“Indeed, tumours with positive responses to checkpoint blockade therapy have increased levels of inflammatory chemokines 72,89,90 .”
BackgroundDendritic Cells, the T-cell-inflamed Tumor Microenvironment, and Immunotherapy Treatment Response
Garris, C., & Luke, J. J. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1321 · Cited by 146
“Anti-PD-1 responsivemouse tumors such as MC38 andMCA1956 had substantially higher CXCL9 and CXCL10 producing DCs compared with anti-PD-1 resistant models such as B16F10 and AT-3, and patients responding to antiPD-1 had higher induction of these chemokines (8).”
BackgroundBrowaeys, R., Gilis, J., Sang-aram, C., Bleser, P. D., Hoste, L., Tavernier, S. J., Lambrechts, D., Seurinck, R., & Saeys, Y. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.13.544751 · Cited by 136
CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer
Marcovecchio, P., Thomas, G. D., & Salek‐Ardakani, S. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002045 · Cited by 137
The therapeutic implications of immunosuppressive tumor aerobic glycolysis
Reinfeld, B. I., Rathmell, W. K., Kim, T. K., & Rathmell, J. C. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00727-3 · Cited by 135
Chibaya, L., Murphy, K. C., DeMarco, K. D., Gopalan, S., Liu, H., Parikh, C. N., Lopez-Diaz, Y., Faulkner, M., Li, J., Morris, J. P., et al. (2023) · Nature Cancer · doi:10.1038/s43018-023-00553-8 · Cited by 138
Role of chemokine systems in cancer and inflammatory diseases
Li, H., Wu, M., & Zhao, X. (2022) · MedComm · doi:10.1002/mco2.147 · Cited by 134
Harnessing the chemokine system to home CAR-T cells into solid tumors
Foeng, J., Comerford, I., & McColl, S. R. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100543 · Cited by 133
“Meanwhile CXCR6-transduced mesothelin-targeting CAR-T cells significantly inhibited tumor growth of patientderived pancreatic cancer xenografts in immunocompromised mice and produced significantly higher levels of IFNg upon in vitro stimulation with patient-derived organoids (compared with control CAR-T cells and cont…”
ResultInfluentialMechanisms of resistance to immune checkpoint inhibitors in melanoma: What we have to overcome?
Ziogas, D. C., Theocharopoulos, C., Koutouratsas, T., Haanen, J. B. A. G., & Gogas, H. J. (2022) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2022.102499 · Cited by 122
Zheng, H., Peng, X., Yang, S., Li, X., Huang, M., Wei, S., Zhang, S., He, G., Liu, J., Fan, Q., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01356-7 · Cited by 126
Turning cold into hot: emerging strategies to fire up the tumor microenvironment
Ma, K., Wang, L., Li, W., Tang, T., Ma, B., Zhang, L., & Zhang, L. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.011 · Cited by 125
Abdul‐Rahman, T., Ghosh, S., Badar, S. M., Nazir, A., Bamigbade, G. B., Aji, N., Roy, P., kachani, H., Garg, N. K., Lawal, L., et al. (2024) · European journal of medical research · doi:10.1186/s40001-024-01711-z · Cited by 131
“To enhance the expression of these chemokines and cytokines by tumor cDC1s, increased production of IFNγ by effector T cells has been suggested [112, 113].”
BackgroundLim, R. J., Salehi‐Rad, R., Tran, L. M., Oh, M. S., Dumitras, C., Crosson, W. P., Li, R., Patel, T. S., Man, S., Yean, C. E., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101479 · Cited by 120
CXCR6 is required for antitumor efficacy of intratumoral CD8 + T cell
Wang, B., Wang, Y., Sun, X., Deng, G., Huang, W., Wu, X., Gu, Y., Tian, Z., Fan, Z., Xu, Q., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003100 · Cited by 120
The CC and CXC chemokines: major regulators of tumor progression and the tumor microenvironment
Bikfalvi, A., & Billottet, C. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00378.2019 · Cited by 116
Duckworth, B. C., Lafouresse, F., Wimmer, V. C., Broomfield, B. J., Dalit, L., Alexandre, Y. O., Sheikh, A. A., Qin, R. Z., Alvarado, C., Mielke, L. A., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-00878-5 · Cited by 113
The role of CXCR3 and its ligands in cancer
Wang, X., Zhang, Y., Wang, S., Ni, H., Zhao, P., Chen, G., Xu, B., & Yuan, L. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1022688 · Cited by 113
“The previous study by Chow (36) and the CXCR3 blocking experiment in the study by Han (52) both confirmed that the anti-tumor effect of PD-1 blockade therapy was significantly weaken after the loss of CXCR3 signaling.”
BackgroundResultInfluentialQiu, J., Xu, B., Ye, D., Ren, D., Wang, S., Benci, J. L., Xu, Y., Ishwaran, H., Beltra, J., Wherry, E. J., et al. (2023) · Nature Cancer · doi:10.1038/s43018-022-00490-y · Cited by 117
Zhong, Z., Vong, C. T., Chen, F., Tan, H., Zhang, C., Wang, N., Cui, L., Wang, Y., & Feng, Y. (2022) · Medicinal Research Reviews · doi:10.1002/med.21876 · Cited by 113
“CXCR3 and its ligand, chemokine (C‐X‐C motif) ligand (CXCL)9, can facilitate the interactions of CD8 T cells or CD103 DCs within the TME to promote a clinical response to PD‐1 blockade.(71) CXCL10 and CXCL11, other key members of chemokines, are the ligands of CXCR3 stimulated by IFN‐γ to induce T‐cell recruitment and…”
BackgroundCancer cell-intrinsic mechanisms driving acquired immune tolerance
Ghorani, E., Swanton, C., & Quezada, S. A. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.004 · Cited by 116
Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy
Xia, X., Yang, Z., Lu, Q., Liu, Z., Wang, L., Du, J., Li, Y., Yang, D., & Wu, S. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02079-8 · Cited by 112
“For example, combining IL-2 and GM-CSF (granulocyte-macrophage colony-stimulating factor) promotes the expression of CXCR3 (C-X-C motif chemokine receptor), which is a biomarker sensitive to PD-1 blocking [101].”
BackgroundCombined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
Tang, K. H., Li, S., Khodadadi-Jamayran, A., Jen, J., Han, H., Guidry, K., Chen, T., Hao, Y., Fedele, C., Zebala, J. A., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0369 · Cited by 105
Chen, J., Sun, H.-W., Yang, Y., Chen, H., Yu, X.-J., Wu, W., Xu, Y.-T., Jin, L.-L., Wu, X., Xu, J., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00377-3 · Cited by 105
“In addition to the direct effect on TILs, recent studies reported that anti-PD-1 treatment could also drive tumor-infiltrating dendritic cells to produce interleukin (IL)12 and CXCL9, which in turn further strengthened T-cell activity and improved cancer immunotherapy.(14,15) These observations suggested that successf…”
BackgroundImmunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy
van Pul, K. M., Fransen, M. F., van de Ven, R., & de Gruijl, T. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.643291 · Cited by 105
“showed that expression of CXCR3, required for tumor rejection after PD-1 blockade in the MC38 mouse model, was expressed at high levels by progenitor-exhausted or early-effector T cells, whereas it was hardly expressed by terminally exhausted T cells (59).”
BackgroundZhang, X., Wei, Z., Yong, T., Li, S., Bie, N., Li, J., Li, X., Liu, H., Xu, H., Yan, Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41438-9 · Cited by 112
Xiong, A., Zhang, J., Chen, Y., Zhang, Y., & Yang, F. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104239 · Cited by 103
Effects of immune‐related adverse events ( irAEs ) and their treatment on antitumor immune responses
Blum, S. M., Rouhani, S. J., & Sullivan, R. J. (2023) · Immunological Reviews · doi:10.1111/imr.13262 · Cited by 105
Convergent inducers and effectors of T cell paralysis in the tumour microenvironment
Hanahan, D., Michielin, O. A., & Pittet, M. J. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00761-z · Cited by 106
“161,222); however, CXCL9 also attracts T reg cells via CXCR3, which promotes interactions with TADCs and suppresses CD8 + T cell antitumour immunity 223 .”
Oshi, M., Newman, S., Tokumaru, Y., Yan, L., Matsuyama, R., Kaliński, P., Endo, I., & Takabe, K. (2020) · Cancers · doi:10.3390/cancers12113342 · Cited by 97
“Tumor-resident DCs regulate and maintain T cell activation during therapy [42,43].”
BackgroundOzga, A. J., Chow, M. T., Lopes, M. E., Servis, R. L., Pilato, M. D., Dehio, P., Lian, J., Mempel, T. R., & Luster, A. D. (2021) · Immunity · doi:10.1016/j.immuni.2021.11.002 · Cited by 96
Self-citationLiu, Y., Zhang, Z., Wang, B., Dong, Y., Zhao, C., Zhao, Y., Zhang, L., Liu, X., Guo, J., Chen, Y., et al. (2022) · Small · doi:10.1002/smll.202107354 · Cited by 98
Imaging of T-cells and their responses during anti-cancer immunotherapy
Krekorian, M., Fruhwirth, G. O., Srinivas, M., Figdor, C. G., Heskamp, S., Witney, T. H., & Aarntzen, E. H. J. G. (2019) · Theranostics · doi:10.7150/thno.37924 · Cited by 99
“For example, chemokine C-X-C receptor 3 (CXCR3), a receptor for the chemokines CXCL9 and CXCL10 expressed on endothelial cell surfaces, mediates T-cell extravasation and engraftment in the tumour [39-42].”
BackgroundCytotoxic T cells swarm by homotypic chemokine signalling
Niño, J. L. G., Pageon, S. V., Tay, S. S., Colakoglu, F., Kempe, D., Hywood, J. D., Mazalo, J. K., Cremasco, J., Govendir, M., Dagley, L. F., et al. (2020) · eLife · doi:10.7554/elife.56554 · Cited by 98
Li, X., Lu, M., Yuan, M., Ye, J., Zhang, W., Xu, L., Wu, X., Hui, B., Yang, Y., Wei, B., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2118210 · Cited by 97
“Previous reports, our previous studies and CXCR3 blocking experiments in the present study all confirmed that the antitumour effect of PD-1 blocking therapy was significantly weakened after the CXCR3 signaling was lost.(13,38)”
Result
Metadata
- Authors
- Chow, M. T., Ozga, A. J., Servis, R. L., Frederick, D. T., Lo, J. A., Fisher, D. E., Freeman, G. J., Boland, G. M., & Luster, A. D.
- Affiliations
- Harvard University (US)
- Corresponding author
- Luster, Andrew D.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 50
- Issue
- 6
- Pages
- 1498-1512.e5
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC6527362
- OpenAlex
- W2945224722
- Cited by
- 716
- References
- 57
- Citations by year
- 2026: 83 · 2025: 98 · 2024: 120 · 2023: 128 · 2022: 96 · 2021: 90 · 2020: 81 · 2019: 19
- FWCI
- 30.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (AR043369)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institutes of Health (AR043369, CA204028, AI112521, CA222871, CA163222)
- Melanoma Research Alliance
- Cancer Research Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- CXCR3, CXCL9, anti-PD-1 therapy, chemokine system, CD8+ T cells, CD103+ dendritic cells, dendritic cell-T cell interaction, tumor microenvironment, melanoma, predictive biomarkers, immunotherapy resistance
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Disease Models, Animal, Humans, Lymphocyte Activation, Neoplasms, Biomarkers, T-Lymphocyte Subsets, Mice, Knockout, CD8-Positive T-Lymphocytes, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Mice, Receptors, CXCR3, Immunomodulation, Molecular Targeted Therapy, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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