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Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade
Open accessAbstract
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.
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“IFN γ and TNF α are key effector cytokines that contribute to anti-tumour immune responses 9,11,27-30 , and genes associated with IFN and TNF signaling pathways contribute to immune evasion 4,9,29 .”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [28]
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“Chronic IFN signaling can also promote an immune suppressive environment126.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [126]
In the citing paper
“The expression of PD-L1 and MHC II, which may cause exhaustion by binding to T-cell programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 (LAG-3), respectively, is regulated by tumor interferon (IFN) signaling.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [24]
In the citing paper
“In solid tumors, a tumor IFN–stimulated gene signature termed ISG.RS is associated with a multigenic program of T-cell exhaustion and worse outcomes after immune checkpoint blockade.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [24]
In the citing paper
“One part of this program is to increase tumor expression of multiple T-cell ligands that lead to exhaustion of T cells infiltrating the TME.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [24]
In the citing paper
“When tumors express a gene signature (ISG.RS) consisting of genes coordinately activated by multiple types of IFN, a multigenic therapy resistance program is activated.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [24]
In the citing paper
“Recently, the Minn group elucidated how chronic IFN signaling mediates immunosuppression and resistance to radiation and immune checkpoint inhibitor therapy in solid tumors.2,24,54”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [24]
In the citing paper
“interferon signaling is of central importance to antitumor immune response43.”
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Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., et al. (2015) · Science · doi:10.1126/science.aaa1348 · Cited by 7,802
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. (2014) · Nature · doi:10.1038/nature13954 · Cited by 6,609
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013) · Nature Methods · doi:10.1038/nmeth.2688 · Cited by 6,422
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
Herbst, R. S., Soria, J.-C., Kowanetz, M., Fine, G. D., Hamid, O., Gordon, M. S., Sosman, J. A., McDermott, D. F., Powderly, J. D., Gettinger, S. N., et al. (2014) · Nature · doi:10.1038/nature14011 · Cited by 5,231
Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652
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
Molecular and genetic properties of tumors associated with local immune cytolytic activity
Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G., & Hacohen, N. (2015) · Cell · doi:10.1016/j.cell.2014.12.033 · Cited by 3,825
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
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma
Zaretsky, J. M., Garcia-Diaz, A., Shin, D. S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D. Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1604958 · Cited by 3,237
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer
Twyman-Saint Victor, C., Rech, A. J., Maity, A., Rengan, R., Pauken, K. E., Stelekati, E., Benci, J. L., Xu, B., Dada, H., Odorizzi, P. M., et al. (2015) · Nature · doi:10.1038/nature14292 · Cited by 2,434
Self-citationMPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
Powles, T. B., Eder, J. P., Fine, G. D., Braiteh, F. S., Loriot, Y., Cruz, C., Joaquim Bellmunt, B., Burris, H. A., Petrylak, D. P., Teng, S.-L. M., et al. (2014) · Nature · doi:10.1038/nature13904 · Cited by 2,410
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
Fulminant Myocarditis with Combination Immune Checkpoint Blockade
Johnson, D. B., Balko, J. M., Compton, M. L., Chalkias, S., Gorham, J., Xu, Y., Hicks, M., Puzanov, I., Alexander, M. R., Bloomer, T. L., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1609214 · Cited by 2,308
Taube, J. M., Anders, R. A., Young, G. D., Xu, H., Sharma, R., McMiller, T. L., Chen, S., Klein, A. P., Pardoll, D. M., Topalian, S. L., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003689 · Cited by 2,157
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy
Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., et al. (2016) · Nature · doi:10.1038/nature19330 · Cited by 2,070
Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J. (2009) · Nature Immunology · doi:10.1038/ni.1679 · Cited by 2,062
Self-citationSpranger, S., Spaapen, R. M., Zha, Y., Williams, J., Meng, Y., Ha, T. T., & Gajewski, T. F. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006504 · Cited by 1,677
Mittal, D., Gubin, M. M., Schreiber, R. D., & Smyth, M. J. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.01.004 · Cited by 1,471
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., et al. (2016) · Science · doi:10.1126/science.aaf2807 · Cited by 1,348 · cited 2×
“In chronic viral infection models, PD1 blockade of PD1highEomes+ TEX fails to convert these cells into durable and self-renewing memory T cells (Pauken et al., 2016).”
Self-citationLoss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy
Gao, J., Shi, L. Z., Zhao, H., Chen, J., Xiong, L., He, Q., Chen, T., Roszik, J., Bernatchez, C., Woodman, S. E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.069 · Cited by 1,300
Overcoming T cell exhaustion in infection and cancer
Pauken, K. E., & Wherry, E. J. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.008 · Cited by 1,220
Self-citationUtzschneider, D. T., Charmoy, M., Chennupati, V., Pousse, L., Ferreira, D. P., Calderon-Copete, S. P., Danilo, M., Alfei, F., Hofmann, M., Wieland, D., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.021 · Cited by 1,095
Type I interferon is selectively required by dendritic cells for immune rejection of tumors
Diamond, M. S., Kinder, M., Matsushita, H., Mashayekhi, M., Dunn, G. P., Archambault, J. M., Lee, H., Arthur, C. D., White, J. M., Kalinke, U., et al. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20101158 · Cited by 1,081
Random forests for genomic data analysis
Chen, X., & Ishwaran, H. (2012) · Genomics · doi:10.1016/j.ygeno.2012.04.003 · Cited by 988
Self-citationProgenitor and Terminal Subsets of CD8 + T Cells Cooperate to Contain Chronic Viral Infection
Paley, M., Kroy, D. C., Odorizzi, P. M., Johnnidis, J. B., Dolfi, D. V., Barnett, B. E., Bikoff, E. K., Robertson, E. J., Lauer, G. M., Reiner, S. L., et al. (2012) · Science · doi:10.1126/science.1229620 · Cited by 903
Self-citationThe Continuum of Cancer Immunosurveillance: Prognostic, Predictive, and Mechanistic Signatures
Galon, J., Angell, H. K., Bedognetti, D., & Marincola, F. M. (2013) · Immunity · doi:10.1016/j.immuni.2013.07.008 · Cited by 887
STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade
Fu, J., Kanne, D. B., Leong, M., Glickman, L. H., McWhirter, S. M., Lemmens, E., Mechette, K., Leong, J. J., Lauer, P., Liu, W., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa4306 · Cited by 720
Blockade of chronic type I interferon signaling to control persistent LCMV infection
Wilson, E. B., Yamada, D. H., Elsaesser, H., Herskovitz, J., Deng, J., Cheng, G., Aronow, B. J., Karp, C. L., & Brooks, D. G. (2013) · Science · doi:10.1126/science.1235208 · Cited by 709
Dighe, A. S., Richards, E., Old, L. J., & Schreiber, R. D. (1994) · Immunity · doi:10.1016/1074-7613(94)90087-6 · Cited by 663
Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection
He, R., Hou, S., Liu, C., Zhang, A.-L., Bai, Q., Han, M., Yang, Y., Wei, G., Shen, T., Yang, X.-X., et al. (2016) · Nature · doi:10.1038/nature19317 · Cited by 643
Weichselbaum, R. R., Ishwaran, H., Yoon, T., Nuyten, D. S. A., Baker, S. W., Khodarev, N. N., Su, A. W., Shaikh, A. Y., Roach, P., Kreike, B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809242105 · Cited by 618
Self-citationSelective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade
Blackburn, S. D., Shin, H., Freeman, G. J., & Wherry, E. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801497105 · Cited by 593
Self-citationTGFβ is a master regulator of radiation therapy-induced antitumor immunity
Vanpouille-Box, C., Diamond, J. M., Pilones, K. A., Zavadil, J., Babb, J. S., Formenti, S. C., Barcellos-Hoff, M. H., & Demaria, S. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3511 · Cited by 514
Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression
Utay, N. S., Bosinger, S. E., Estes, J. D., Zhu, R. T., Tharp, G. K., Boritz, E., Levin, D., Wijeyesinghe, S., Nganou‐Makamdop, K., Prete, G. Q. D., et al. (2014) · Nature · doi:10.1038/nature13554 · Cited by 458
High-Dimensional Variable Selection for Survival Data
Ishwaran, H., Kogalur, U. B., Gorodeski, E. Z., Minn, A. J., & Lauer, M. S. (2010) · Journal of the American Statistical Association · doi:10.1198/jasa.2009.tm08622 · Cited by 457
Self-citationUnphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes
Cheon, H., & Stark, G. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903487106 · Cited by 306
Combination Cancer Therapies with Immune Checkpoint Blockade: Convergence on Interferon Signaling
Minn, A. J., & Wherry, E. J. (2016) · Cell · doi:10.1016/j.cell.2016.03.031 · Cited by 270
Self-citationBlockade of Interferon Beta, but Not Interferon Alpha, Signaling Controls Persistent Viral Infection
Ng, C. T., Sullivan, B. M., Teijaro, J. R., Lee, A. M., Welch, M., Rice, S., Sheehan, K. C. F., Schreiber, R. D., & Oldstone, M. B. A. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.04.005 · Cited by 172
Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment
Gajewski, T. F., Fuertes, M. B., Spaapen, R. M., Zheng, Y., & Kline, J. P. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.11.013 · Cited by 138
McWilliams, J. A., McGurran, S. M., DOW, S. W., Slansky, J. E., & Kedl, R. M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.1.155 · Cited by 41
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Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy
Sharma, P., Hu-Lieskovan, S., Wargo, J. A., & Ribas, A. (2017) · Cell · doi:10.1016/j.cell.2017.01.017 · Cited by 5,588
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., Kadel III, E. E., Koeppen, H., Astarita, J. L., Cubas, R., et al. (2018) · Nature · doi:10.1038/nature25501 · Cited by 5,400
Approaches to treat immune hot, altered and cold tumours with combination immunotherapies
Galon, J., & Bruni, D. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0007-y · Cited by 3,520
The immune contexture in cancer prognosis and treatment
Fridman, W. H., Zitvogel, L., Sautès–Fridman, C., & Kroemer, G. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.101 · Cited by 2,263
The diverse functions of the PD1 inhibitory pathway
Sharpe, A. H., & Pauken, K. E. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.108 · Cited by 2,054
Self-citation
Metadata
- Authors
- Benci, J. L., Xu, B., Qiu, Y., Wu, T. J., Dada, H., Twyman-Saint Victor, C., Cucolo, L., Lee, D. S. M., Pauken, K. E., Huang, A. C., Gangadhar, T. C., Amaravadi, R. K., Schuchter, L. M., Feldman, M. D., Ishwaran, H., Vonderheide, R. H., Maity, A., Wherry, E. J., & Minn, A. J.
- Affiliations
- University of Pennsylvania (US)
- University of Miami (US)
- Parker Institute for Cancer Immunotherapy (US)
- Corresponding author
- Minn, Andy J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 167
- Issue
- 6
- Pages
- 1540-1554.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5385895
- OpenAlex
- W2558219863
- Cited by
- 1,216
- References
- 42
- Citations by year
- 2026: 150 · 2025: 124 · 2024: 127 · 2023: 135 · 2022: 128 · 2021: 140 · 2020: 140 · 2019: 114 · 2018: 92 · 2017: 64 · 2016: 1
- FWCI
- 48.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo
- Funders
- Melanoma Research Alliance
- Parker Institute for Cancer Immunotherapy
- Robertson Foundation
- Cancer Research Institute Irvington Fellowship
- NIH (P50CA174523, R01CA163739, R01CA158186, P30CA016520, U19AI082630, R01AI105343, U01AI095608, P01AI112521)
- Basser Research Center for BRCA
- Abramson Cancer Center Translational Center of Excellence in Pancreatic Cancer
- Department of Defense Era of Hope Scholar (W81XWH-09-1-0339)
- NCI (R01CA172651)
- Merck
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immune checkpoint inhibitor resistance, type I interferon, interferon-gamma, PD-1 pathway, PD-L1, STAT1, interferon-stimulated genes, T cell inhibitory receptors, T cell exhaustion, radiotherapy, tumor immune microenvironment, resistance biomarkers, anti-PD-1 therapy
- MeSH terms
- Animals, Humans, Interferons, Melanoma, Neoplasm Transplantation, T-Lymphocytes, Radioimmunotherapy, Drug Resistance, Neoplasm, Cell Line, Tumor, STAT1 Transcription Factor, Mice, B7-H1 Antigen, CTLA-4 Antigen, Heterografts
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