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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CXCL10 has been shown to promote effector T cell generation and function.
“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]
The Discussion (page unavailable) states that CD11b+ dendritic cell-derived CXCL10 is essential for optimal generation of CD4+ Th1 responses, supporting the generation part. The Introduction discusses T-cell function for the CXCR3 chemokine system generally, but does not establish that CXCL10 specifically promotes effector T-cell function. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCXCL9, CXCL10, and CXCL11 are CXCR3 ligands that promote trafficking of CD8+CXCR3+ T cells into tumors.
“CXCL9/10/11 are ligands of the CXCR3 receptor involved in increased trafficking of CD8+CXCR3+ T cells to tumors (47,48,64).”
The CXCL9/10/11-CXCR3 pathway is well known for recruiting and activating cytotoxic T cells.
“The relevance of the CXCL9/10/11-CXCR3 pathway for recruiting and triggering cytotoxic T cells is well known (47-50,64).”
CXCR3 is not required for early CD8+ T-cell recruitment into tumors.
“Data suggest that CXCR3 is not essential for the early recruitment of CD8+ T cells into tumors (64).”
CXCR3 ligands are reported to act as both biomarkers and inducers of response to anti-PD-1 alone or with anti-CTLA-4.
“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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“It has been suggested that the efficacy of immune checkpoint blockade relies on T cells already present in tumors, given that FTY720 administration before treatment did not affect the efficacy of immunotherapy (Garris et al., 2018; Siddiqui et al., 2019; Spranger et al., 2014; Wang et al., 2016).”
Sung, J. H., Zhang, H., Moseman, E. A., Álvarez, D., Iannacone, M., Henrickson, S. E., de la Torre, J. C., Groom, J. R., Luster, A. D., & von Andrian, U. H. (2012) · Cell · doi:10.1016/j.cell.2012.08.015 · Cited by 228 · cited 4× · see citing works
“The CXCR3 chemokine system also plays important roles in the positioning of T cells within secondary lymphoid organs and peripheral tissue, facilitating the interactions of T cells with antigen-loaded activated dendritic cells (DCs), promoting T cell activation and differentiation, as well as assisting the process of…”
InfluentialSelf-citationKastenmüller, W., Brandes, M., Wang, Z., Herz, J., Egen, J. G., & Germain, R. N. (2013) · Immunity · doi:10.1016/j.immuni.2012.11.012 · Cited by 225 · see citing works
Hickman, H. D., Reynoso, G. V., Ngudiankama, B. F., Cush, S. S., Gibbs, J. S., Bennink, J. R., & Yewdell, J. W. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.009 · Cited by 218 · cited 2× · see citing works
“The CXCR3 chemokine system also plays important roles in the positioning of T cells within secondary lymphoid organs and peripheral tissue, facilitating the interactions of T cells with antigen-loaded activated dendritic cells (DCs), promoting T cell activation and differentiation, as well as assisting the process of…”
Christen, U., McGavern, D. B., Luster, A. D., von Herrath, M. G., & Oldstone, M. B. A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.12.6838 · Cited by 179 · see citing works
Self-citationBerghuis, D., Santos, S. J., Baelde, H. J., Taminiau, A. H. M., Egeler, R. M., Schilham, M. W., Hogendoorn, P. C. W., & Lankester, A. C. (2010) · The Journal of Pathology · doi:10.1002/path.2819 · Cited by 159 · cited 2× · see citing works
“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”
Maximal T Cell–Mediated Antitumor Responses Rely upon CCR5 Expression in Both CD4+ and CD8+ T Cells
González-Martín, A., Gómez, L., Lustgarten, J., Mira, E., & Mañes, S. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1687 · Cited by 137 · cited 2× · see citing works
“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”
Park, M. K., Amichay, D., Love, P. E., Wick, E., Liao, F., Grinberg, A., Rabin, R. L., Zhang, H. H., Gebeyehu, S., Wright, T. M., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.3.1433 · Cited by 132 · see citing works
Liu, J., Li, F., Yü, P., Wang, L., Chen, X., Wang, D., Cao, L., Zhao, S. Q., Li, B., Kaliński, P., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4617 · Cited by 118 · cited 2× · see citing works
“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”
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Dendritic cells in cancer immunology and immunotherapy
Wculek, S. K., Cueto, F. J., Mujal, A. M., Melero, I., Krummel, M. F., & Sancho, D. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0210-z · Cited by 2,594 · see citing works
The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy
Bruni, D., Angell, H. K., & Galon, J. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0285-7 · Cited by 1,586 · see citing works
Clinical implications of T cell exhaustion for cancer immunotherapy
Chow, A., Perica, K., Klebanoff, C. A., & Wolchok, J. D. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00689-z · Cited by 1,044 · see citing works
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition
Litchfield, K., Reading, J. L., Puttick, C., Thakkar, K., Abbosh, C., Bentham, R., Watkins, T. B. K., Rosenthal, R., Biswas, D., Rowan, A., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.002 · Cited by 893 · see citing works
Spatially organized multicellular immune hubs in human colorectal cancer
Pelka, K., Hofree, M., Chen, J. H., Sarkizova, S., Pirl, J. D., Jorgji, V., Bejnood, A., Dionne, D. A., Ge, W. H., Xu, K. H., et al. (2021) · Cell · doi:10.1016/j.cell.2021.08.003 · Cited by 902 · see citing works
“Supporting this notion, recent studies showed that expression of CXCR3 chemokines in myeloid cells is required for inducing anti-tumor T cell responses following checkpoint inhibitor treatment in mice (Chow et al., 2019; House et al., 2020).”
ResultSelf-citationChemokines and the immune response to cancer
Ozga, A. J., Chow, M. T., & Luster, A. D. (2021) · Immunity · doi:10.1016/j.immuni.2021.01.012 · Cited by 849 · see citing works
Self-citationTurning Cold into Hot: Firing up the Tumor Microenvironment
Duan, Q., Zhang, H., Zheng, J., & Zhang, L. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.02.022 · Cited by 934 · see citing works
A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer
Bassez, A., Vos, H., Van Dyck, L., Floris, G., Arijs, I., Desmedt, C., Boeckx, B., Vanden Bempt, M., Nevelsteen, I., Lambein, K., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01323-8 · Cited by 867 · see citing works
House, I. G., Savas, P., Lai, J., Chen, A. X. Y., Oliver, A. J., Teo, Z. L., Todd, K. L., Henderson, M. A., Giuffrida, L., Petley, E. V., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1868 · Cited by 790 · see citing works
“We believe one explanation for this apparent discrepancy is that while macrophages are critical for CXCR3-dependent recruitment of T cells through their production of CXCL9/10 in the tumor, CXCL9/10 production by other myeloid subsets, including CD103þ DCs, is likely to be important for T-cell priming both within the…”
BackgroundInfluentialCold and hot tumors: from molecular mechanisms to targeted therapy
Wu, B., Zhang, B., Li, B., Wu, H., & Jiang, M. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01979-x · Cited by 751 · see citing works
CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers
Bill, R., Wirapati, P., Messemaker, M., Roh, W., Zitti, B., Duval, F., Kiss, M., Park, J. C., Saal, T. M., Hoelzl, J., et al. (2023) · Science · doi:10.1126/science.ade2292 · Cited by 685 · see citing works
Key chemokines direct migration of immune cells in solid tumors
Kohli, K., Pillarisetty, V. G., & Kim, T. S. (2022) · Cancer Gene Therapy · doi:10.1038/s41417-021-00303-x · Cited by 583 · see citing works
The cancer–natural killer cell immunity cycle
Huntington, N. D., Cursons, J., & Rautela, J. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0272-z · Cited by 574 · see citing works
Engineering dendritic cell vaccines to improve cancer immunotherapy
Perez, C. R., & Palma, M. D. (2019) · Nature Communications · doi:10.1038/s41467-019-13368-y · Cited by 507 · see citing works
CD8+ T Cell Exhaustion in Cancer
Dolina, J. S., Budimir, N., Thomas, G. D., & Salek‐Ardakani, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.715234 · Cited by 487 · see citing works
Dendritic Cells and Their Role in Immunotherapy
Gardner, A., Pulido, Á. D. M., & Ruffell, B. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00924 · Cited by 485 · see citing works
“As CXCL9 expression also correlates with response to anti-PD-1 (14), there is likely a critical role for cDC1s in the context of patient response to ICB as well, although this has not been directly tested.”
BackgroundCXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
Di Pilato, M., Kfuri-Rubens, R., Pruessmann, J. N., Ozga, A. J., Messemaker, M., Cadilha, B. L., Sivakumar, R., Cianciaruso, C., Warner, R. D., Marangoni, F., et al. (2021) · Cell · doi:10.1016/j.cell.2021.07.015 · Cited by 488 · see citing works
Self-citationAndersson, A., Larsson, L., Stenbeck, L., Salmén, F., Ehinger, A., Wu, S. Z., Al-Eryani, G., Roden, D., Swarbrick, A., Borg, Å., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26271-2 · Cited by 404 · see citing works
A neutrophil response linked to tumor control in immunotherapy
Gungabeesoon, J., Gort-Freitas, N. A., Kiss, M., Bolli, E., Messemaker, M., Siwicki, M. R., Hicham, M., Bill, R., Koch, P. D., Cianciaruso, C., et al. (2023) · Cell · doi:10.1016/j.cell.2023.02.032 · Cited by 416 · see citing works
Zhou, Y., Fei, M., Zhang, G., Liang, W., Lin, W., Wu, Y., Piskol, R., Ridgway, J. B., McNamara, E., Huang, H., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.01.014 · Cited by 399 · see citing works
Dendritic cells as orchestrators of anticancer immunity and immunotherapy
Heras‐Murillo, I., Adán‐Barrientos, I., Galán, M. Á., Wculek, S. K., & Sancho, D. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-024-00859-1 · Cited by 403 · see citing works
“T cell interactions by enhancing the expression of CXCR3 on T cells and production of its ligand CXCL9 by DCs 132,155 (Fig.”
Leader, A. M., Grout, J. A., Maier, B. B., Nabet, B. Y., Park, M. D., Tabachnikova, A., Chang, C., Walker, L. A., Lansky, A., Bérichel, J. L., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.10.009 · Cited by 357 · see citing works
Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy
Lü, Q., Kou, D., Lou, S., Ashrafizadeh, M., Aref, A. R., Cañadas, I., Tian, Y., Niu, X., Wang, Y. Z., Torabian, P., et al. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01535-8 · Cited by 376 · see citing works
Exploring immunotherapy in colorectal cancer
Weng, J., Li, S., Zhu, Z., Liu, Q., Zhang, R., Yang, Y., & Li, X. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01294-4 · Cited by 355 · see citing works
“In particular, CXCR3 has been identified as a chemokine receptor critical for T cell infiltration [67].”
BackgroundPD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program
Hashimoto, M., Araki, K., Cardenas, M. A., Li, P., Jadhav, R. R., Kissick, H. T., Hudson, W. H., McGuire, D. J., Obeng, R. C., Wieland, A., et al. (2022) · Nature · doi:10.1038/s41586-022-05257-0 · Cited by 323 · see citing works
“CXCR3 plays an important role in CD8 + T-cell mediated viral control and a role for CXCL9 and CXCL10 has been implicated in cancer immunotherapy 21,22 .”
BackgroundSelf-citationDendritic cells as shepherds of T cell immunity in cancer
Pittet, M. J., Pilato, M. D., Garris, C., & Mempel, T. R. (2023) · Immunity · doi:10.1016/j.immuni.2023.08.014 · Cited by 326 · 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 315 · see citing works
Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade
Budimir, N., Thomas, G. D., Dolina, J. S., & Salek‐Ardakani, S. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-21-0515 · Cited by 302 · see citing works
“Using Cxcr3deficient mice, Chow and colleagues demonstrated that the CXCR3– CXCL9 axis represents a limiting factor of anti–PD-1 efficacy in the murineMC38model (54).”
BackgroundThe role of dendritic cells in cancer and anti-tumor immunity
Marciscano, A. E. E., & Anandasabapathy, N. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101481 · Cited by 305 · see citing works
How chemokines organize the tumour microenvironment
Mempel, T. R., Lill, J. K., & Altenburger, L. M. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00635-w · Cited by 306 · see citing works
“using fusions of tumour antigens to CCL20 to target CCR6-expressing APCs 277 .”
InfluentialPD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells
Deak, L. C., Nicolini, V., Hashimoto, M., Karagianni, M., Schwalie, P. C., Lauener, L., Varypataki, E. M., Richard, M., Bommer, E., Sam, J., et al. (2022) · Nature · doi:10.1038/s41586-022-05192-0 · Cited by 277 · see citing works
CXCR3 Ligands in Cancer and Autoimmunity, Chemoattraction of Effector T Cells, and Beyond
Karin, N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00976 · Cited by 281 · see citing works
“Only recently it has been suggested that that CXCL9 is also involved in directing the potentiation of CD8+ T cells in cancer, and that its activity differs from CCL10 (7).”
BackgroundMiddleton, M. R., McAlpine, C., Woodcock, V. K., Corrie, P. G., Infante, J. R., Steven, N. M., Evans, T. R. J., Anthoney, A., Shoushtari, A. N., Hamid, O., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1247 · Cited by 276 · see citing works
“A role of this axis in the sensitivity to anti–PD-1 therapy has also been indicated (25).”
BackgroundPulido, Á. D. M., Hänggi, K., Celias, D. P., Gardner, A., Li, J., Bittencourt, B. M. B., Mohamed, E. T., Trillo-Tinoco, J., Osunmakinde, O., Peña, R. J., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.04.019 · Cited by 272 · see citing works
Cancer immune evasion, immunoediting and intratumour heterogeneity
Roerden, M., & Spranger, S. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-024-01111-8 · Cited by 286 · see citing works
Hoch, T., Schulz, D., Eling, N., Gómez, J. M. M., Levesque, M. P., & Bodenmiller, B. (2022) · Science Immunology · doi:10.1126/sciimmunol.abk1692 · Cited by 246 · see citing works
Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade
Bonavita, E., Bromley, C. P., Jonsson, G., Pelly, V. S., Sahoo, S., Walwyn-Brown, K., Mensurado, S., Moeini, A., Flanagan, E., Bell, C. R., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.10.020 · Cited by 252 · see citing works
“This switch in the molecular profile of TAMs toward IFN-g signaling was also evident by bulk tumor RNA sequencing and, crucially, depended on NK cell presence (Figure 3A).”
BackgroundInfluentialFOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy
Chan, J. D., Scheffler, C. M., Munoz, I., Sek, K., Lee, J. N., Huang, Y., Yap, K. M., Saw, N. Y. L., Li, J., Chen, A. X. Y., et al. (2024) · Nature · doi:10.1038/s41586-024-07242-1 · Cited by 251 · see citing works
Tumor-infiltrating dendritic cell states are conserved across solid human cancers
Gerhard, G. M., Bill, R., Messemaker, M., Klein, A. M., & Pittet, M. J. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20200264 · Cited by 240 · see citing works
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Xia, Y., Tang, W., Qian, X., Li, X., Cheng, F., Wang, K., Zhang, F., Zhang, C., Li, D., Song, J., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004656 · Cited by 228 · see citing works
Pelly, V. S., Moeini, A., Roelofsen, L. M., Bonavita, E., Bell, C. R., Hutton, C., Blanco‐Gómez, A., Banyard, A., Bromley, C. P., Flanagan, E., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1815 · Cited by 226 · see citing works
“Addition of CXB reduced the production of pro-tumorigenic mediators such as IL6 or CXCL1 while concomitantly enhancing the release of CXCL9 and CXCL10, major IFN-γ-driven CTL-chemoattractants essential for natural and therapy-induced anti-tumor immunity (47).”
BackgroundTGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking
Gunderson, A. J., Yamazaki, T., McCarty, K., Fox, N., Phillips, M., Alice, A. F., Blair, T. C., Whiteford, M. H., O’Brien, D. P., Ahmad, R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15404-8 · Cited by 223 · see citing works
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Stem-like exhausted and memory CD8+ T cells in cancer
Gebhardt, T., Park, S. L., & Parish, I. A. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00615-0 · Cited by 216 · see citing works
“However, blocking T cell lymph node egress, surgical removal of tumour-draining lymph nodes or disruption of T cell recruitment to the tumour inhibits therapy-induced control 73,214,217–219 .”
BackgroundDinh, H. Q., Pan, F., Wang, G., Huang, Q., Olingy, C. E., Wu, Z., Wang, S., Xu, X., Xu, X., He, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27599-5 · Cited by 210 · see citing works
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Meiser, P., Knolle, M. A., Hirschberger, A., de Almeida, G. P., Bayerl, F., Lacher, S. B., Pedde, A., Flommersfeld, S., Hönninger, J., Stark, L., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.06.008 · Cited by 202 · see citing works
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Human Anti-tumor Immunity: Insights from Immunotherapy Clinical Trials
Egen, J. G., Ouyang, W., & Wu, L. C. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.010 · Cited by 197 · see citing works
Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker
Wang, Z., & Wu, X. (2020) · Cancer Medicine · doi:10.1002/cam4.3410 · Cited by 200 · see citing works
Regulatory cells and the effect of cancer immunotherapy
Iglesias-Escudero, M., Arias-González, N., & Martínez-Cáceres, E. M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01714-0 · Cited by 195 · see citing works
“Synergy of TLR-mediated activation of DCs and ICB can be further improved by FLT3L-mediated expansion of DC populations [141].”
BackgroundInfluentialGomes-Santos, I. L., Amoozgar, Z., Kumar, A. S., Ho, W. W., Roh, K., Talele, N. P., Curtis, H., Kawaguchi, K., Jain, R. K., & Fukumura, D. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0499 · Cited by 181 · see citing works
“CXCL9/10/11 are ligands of the CXCR3 receptor involved in increased trafficking of CD8þCXCR3þ T cells to tumors (47, 48, 64).”
BackgroundThe tumor microenvironment’s role in the response to immune checkpoint blockade
Aliazis, K., Christofides, A., Shah, R., Yeo, Y. Y., Jiang, S., Charest, A., & Boussiotis, V. A. (2025) · Nature Cancer · doi:10.1038/s43018-025-00986-3 · Cited by 203 · see citing works
“The anti-tumor responses to PD-1 blockade are compromised when intratumoral migration of CD8 + T cells lacking the CXCR3 chemokine receptor is impaired 83 , underscoring the mandatory role of intratumoral cDC1–CD8 + T cell cross-talk.”
Chen, J. H., Nieman, L. T., Spurrell, M., Jorgji, V., Elmelech, L., Richieri, P. M., Xu, K. H., Madhu, R., Parikh, M., Zamora, I., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01792-2 · Cited by 184 · see citing works
“Macrophages are major producers of CXCR3 ligands in the tumor microenvironment and that these ligands positively associate with CD8 + T cell infiltration and immunotherapy response 7,41,42 .”
Self-citationDendritic cell maturation in cancer
Moon, C. Y., Belabed, M., Park, M. D., Mattiuz, R., Puleston, D. J., & Mérad, M. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-024-00787-3 · Cited by 186 · see citing works
“For instance, recruitment of activated CXCR3 + CD8 + T cells to the tumour site, which is critical for the response to ICB therapy, has been shown to be dependent on IFNγ-induced expression of CXCL9 and CXCL10 in DCs in a transplantable model of MC38, a mouse colon tumour line 191 .”
Fang, Y., Liu, W.-R., Tang, Z., Ji, X.-D., Zhou, Y., Song, S.-S., Tian, M.-X., Tao, C., Huang, R., Zhu, G., et al. (2022) · Hepatology · doi:10.1002/hep.32348 · Cited by 164 · see citing works
“Substantial evidence has indicated that CXCL9/10‐ CXCR3 mediates the recruitment of T cells, which correlate with improved prognosis in patients with tumors.[32,33] Comparison of transcriptomic profiles of shCtrl and shMCT4 HMCC97H cells revealed that CXCL9 and CXCL10 were up‐regulated in the shMCT4 cells.”
BackgroundBarriers to immune cell infiltration in tumors
Melssen, M. M., Sheybani, N., Leick, K. M., & Slingluff, C. L. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006401 · Cited by 163 · see citing works
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 157 · see citing works
“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 154 · see citing works
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 145 · see citing works
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Trial watch: dendritic cell vaccination for cancer immunotherapy
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“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
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“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 126 · see citing works
CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer
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The therapeutic implications of immunosuppressive tumor aerobic glycolysis
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Role of chemokine systems in cancer and inflammatory diseases
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Harnessing the chemokine system to home CAR-T cells into solid tumors
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“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?
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Turning cold into hot: emerging strategies to fire up the tumor microenvironment
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“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 117 · see citing works
CXCR6 is required for antitumor efficacy of intratumoral CD8 + T cell
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The CC and CXC chemokines: major regulators of tumor progression and the tumor microenvironment
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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 · see citing works
The role of CXCR3 and its ligands in cancer
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“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 111 · see citing works
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“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
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Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy
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“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 · see citing works
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“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
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“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).”
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Effects of immune‐related adverse events ( irAEs ) and their treatment on antitumor immune responses
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Convergent inducers and effectors of T cell paralysis in the tumour microenvironment
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“161,222); however, CXCL9 also attracts T reg cells via CXCR3, which promotes interactions with TADCs and suppresses CD8 + T cell antitumour immunity 223 .”
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“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 98 · see citing works
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Imaging of T-cells and their responses during anti-cancer immunotherapy
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“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 97 · see citing works
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 96 · see citing works
“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
- 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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