Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance
Open accessAbstract
Patients affected by colorectal cancer (CRC) with DNA mismatch repair deficiency (MMRd), often respond to immune checkpoint blockade therapies, while those with mismatch repair-proficient (MMRp) tumors generally do not. Interestingly, a subset of MMRp CRCs contains variable fractions of MMRd cells, but it is unknown how their presence impacts immune surveillance. We asked whether modulation of the MMRd fraction in MMR heterogeneous tumors acts as an endogenous cancer vaccine by promoting immune surveillance. To test this hypothesis, we use isogenic MMRp ( Mlh1 +/+ ) and MMRd ( Mlh1 −/− ) mouse CRC cells. MMRp/MMRd cells mixed at different ratios are injected in immunocompetent mice and tumor rejection is observed when at least 50% of cells are MMRd. To enrich the MMRd fraction, MMRp/MMRd tumors are treated with 6-thioguanine, which leads to tumor rejection. These results suggest that genetic and pharmacological modulation of the DNA mismatch repair machinery potentiate the immunogenicity of MMR heterogeneous tumors.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Enrichment of dMMR clones can be achieved by treatment with chemotherapeutics such as temozolomide and 6-thioguanine, to which dMMR tumour cells show higher intrinsic resistance than pMMR cells.
“Enrichment of dMMR clones can be achieved by treatment with chemotherapeutics such as temozolomide (TMZ) and 6-Thioguanine, to which dMMR tumour cells show higher intrinsic resistance than pMMR cells.153”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [153]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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
Improved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239 · see citing works
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234 · see citing works
Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer
André, T., Shiu, K.-K., Kim, T. W., Jensen, B. V., Jensen, L. H., Punt, C., Smith, D., Garcia-Carbonero, R., Benavides, M., Gibbs, P., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2017699 · Cited by 3,099 · see citing works
Marabelle, A., Le, D. T., Ascierto, P. A., Giacomo, A. M. D., Jesus‐Acosta, A. D., Delord, J., Geva, R., Gottfried, M., Penel, N., Hansen, A. R., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.19.02105 · Cited by 3,077 · see citing works
Li, W., Xu, H., Xiao, T., Cong, L., Love, M. I., Zhang, F., Irizarry, R. A., Liu, J. S., Brown, M., & Liu, X. S. (2014) · Genome Biology · doi:10.1186/s13059-014-0554-4 · Cited by 2,684 · see citing works
Overman, M. J., Lonardi, S., Wong, K. Y. M., Lenz, H.-J., Gelsomino, F., Aglietta, M., Morse, M. A., Van Cutsem, E., McDermott, R., Hill, A., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.76.9901 · Cited by 2,079 · see citing works
Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology
Benson, A. B., Venook, A. P., Al-Hawary, M. M., Arain, M. A., Chen, Y., Ciombor, K. K., Cohen, S. A., Cooper, H. S., Deming, D. A., Farkas, L. M., et al. (2021) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2021.0012 · Cited by 1,709 · see citing works
Kim, S. T., Cristescu, R., Bass, A. J., Kim, K., Odegaard, J. I., Kim, K., Liu, X. Q., Sher, X., Jung, H., Lee, M.-J., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0101-z · Cited by 1,660 · see citing works
The multifaceted mismatch-repair system
Jiricny, J. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1907 · Cited by 1,375 · see citing works
Dijkstra, K. K., Cattaneo, C. M., Weeber, F., Chalabi, M., van de Haar, J., Fanchi, L. F., Slagter, M., van der Velden, D. L., Kaing, S., Kelderman, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.009 · Cited by 1,135 · see citing works
Self-citationLuchini, C., Bibeau, F., Ligtenberg, M. J. L., Singh, N., Nottegar, A., Bosse, T., Miller, R. E., Riaz, N., Douillard, J.-Y., André, F., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz116 · Cited by 1,044 · see citing works
Classification and characterization of microsatellite instability across 18 cancer types
Hause, R. J., Pritchard, C. C., Shendure, J., & Salipante, S. J. (2016) · Nature Medicine · doi:10.1038/nm.4191 · Cited by 982 · see citing works
Turajlic, S., Litchfield, K., Xu, H., Rosenthal, R., McGranahan, N., Reading, J. L., Wong, Y. N. S., Rowan, A., Kanu, N., Bakir, M. A., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30516-8 · Cited by 909 · see citing works
A molecular portrait of microsatellite instability across multiple cancers
Cortés‐Ciriano, I., Lee, S., Park, W., Kim, T., & Park, P. J. (2017) · Nature Communications · doi:10.1038/ncomms15180 · Cited by 651 · see citing works
Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth
Germano, G., Lamba, S., Rospo, G., Barault, L., Magrì, A., Maione, F., Russo, M., Crisafulli, G., Bartolini, A., Lerda, G., et al. (2017) · Nature · doi:10.1038/nature24673 · Cited by 627 · see citing works
Self-citationCahill, D. P., Levine, K. K., Betensky, R. A., Codd, P. J., Romany, C. A., Reavie, L. B., Batchelor, T. T., Futreal, P. A., Stratton, M. R., Curry, W. T., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2149 · Cited by 450 · see citing works
Yip, S. S. F., Miao, J., Cahill, D. P., Iafrate, A. J., Aldape, K., Nutt, C. L., & Louis, D. N. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-3012 · Cited by 403 · see citing works
The Spectrum of Benefit from Checkpoint Blockade in Hypermutated Tumors
Rousseau, B., Foote, M. B., Maron, S. B., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmc2031965 · Cited by 213 · see citing works
Beamer, L. C., Grant, M. L., Espenschied, C. R., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.38.4719 · Cited by 202 · see citing works
McCarthy, A. J., Capo‐Chichi, J., Spence, T., Grenier, S., Stockley, T. L., Kamel‐Reid, S., Serra, S., Sabatini, P. J. B., & Chetty, R. (2018) · The Journal of Pathology Clinical Research · doi:10.1002/cjp2.120 · Cited by 163 · see citing works
Morano, F., Raimondi, A., Pagani, F., Lonardi, S., Salvatore, L., Cremolini, C., Murgioni, S., Randon, G., Palermo, F., Antonuzzo, L., et al. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02583 · Cited by 134 · see citing works
Crisafulli, G., Bianchi, A. S., Lazzari, L., Pietrantonio, F., Amatu, A., Macagno, M., Barault, L., Cassingena, A., Bartolini, A., Luraghi, P., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1434 · Cited by 134 · see citing works
Self-citationThe Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers
Germano, G., Amirouchene-Angelozzi, N., Rospo, G., & Bardelli, A. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0150 · Cited by 128 · see citing works
Self-citationMichel, S., Benner, A., Tariverdian, M., Wentzensen, N., Hoefler, P., Pommerencke, T., Grabe, N., Doeberitz, M. V. K., & Kloor, M. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604756 · Cited by 126 · see citing works
The utility of immunohistochemical detection of DNA mismatch repair gene proteins
Shia, J., Ellis, N. A., & Klimstra, D. S. (2004) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-004-1090-5 · Cited by 109 · see citing works
Heterogenous mismatch-repair status in colorectal cancer
Joost, P., Veurink, N., Holck, S., Klarskov, L. L., Bojesen, A., Harbo, M., Baldetorp, B., Rambech, E., & Nilbert, M. C. (2014) · Diagnostic Pathology · doi:10.1186/1746-1596-9-126 · Cited by 105 · see citing works
Yan, T., Berry, S. E., Desai, A. B., & Kinsella, T. J. (2003) · PubMed · Cited by 104 · see citing works
Unusual Mismatch Repair Immunohistochemical Patterns in Endometrial Carcinoma
Watkins, J. C., Nucci, M. R., Ritterhouse, L. L., Howitt, B. E., & Sholl, L. M. (2016) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000663 · Cited by 92 · see citing works
Prognostic and predictive significance of MSI in stages II/III colon cancer
Saridaki, Z. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i22.6809 · Cited by 86 · see citing works
Pietrantonio, F., Perrone, F., de Braud, F., Castano, A., Maggi, C., Bossi, I., Gevorgyan, A., Biondani, P., Pacifici, M., Busico, A., et al. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt547 · Cited by 86 · see citing works
Fusco, N., Lopez, G., Corti, C., et al. (2018) · JNCI Cancer Spectrum · doi:10.1093/jncics/pky056 · Cited by 81 · see citing works
Amodio, V., Mauri, G., Reilly, N. M., Bianchi, A. S., Siena, S., Bardelli, A., & Germano, G. (2021) · Cancers · doi:10.3390/cancers13112638 · Cited by 67 · see citing works
Self-citationChapusot, C., Martin, L., Bouvier, A., et al. (2002) · British Journal of Cancer · doi:10.1038/sj.bjc.6600474 · Cited by 65 · see citing works
Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge
Marmorino, F., Boccaccino, A., Germani, M. M., Falcone, A., & Cremolini, C. (2020) · Cancers · doi:10.3390/cancers12082317 · Cited by 57 · see citing works
Evensen, N. A., Madhusoodhan, P. P., Meyer, J., Saliba, J., Chowdhury, A., Araten, D. J., Nersting, J., Bhatla, T., Vincent, T. L., Teachey, D. T., et al. (2018) · Haematologica · doi:10.3324/haematol.2017.176362 · Cited by 55 · see citing works
Tachon, G., Frouin, É., Karayan, L., Auriault, M., Godet, J., Moulin, V., Wang, Q., & Tougeron, D. (2018) · European Journal of Cancer · doi:10.1016/j.ejca.2018.01.087 · Cited by 42 · see citing works
Amatu, A., Barault, L., Moutinho, C., Cassingena, A., Bencardino, K. B., Ghezzi, S., Palmeri, L., Bonazzina, E. F., Tosi, F., Ricotta, R., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw071 · Cited by 41 · see citing works
Self-citationScreening Patients With Colorectal Cancer for Lynch Syndrome: What Are We Waiting For?
Kastrinos, F., & Syngal, S. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.40.7171 · Cited by 39 · see citing works
Loupakis, F., Maddalena, G., Depetris, I., Murgioni, S., Bergamo, F., Tos, A. P. D., Rugge, M., Munari, G., Nguyen, A., Szeto, C. W., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0788-5 · Cited by 36 · see citing works
Walbert, T., Gilbert, M. R., Groves, M. D., Puduvalli, V. K., Yung, W. K. A., Conrad, C. A., Bobustuc, G. C., Colman, H., Hsu, S. H., Bekele, B. N., et al. (2010) · Journal of Neuro-Oncology · doi:10.1007/s11060-010-0313-7 · Cited by 32 · see citing works
Pietrantonio, F., Lobefaro, R., Antista, M., Lonardi, S., Raimondi, A., Morano, F., Mosconi, S., Rimassa, L., Murgioni, S., Bianchi, A. S., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3024 · Cited by 32 · see citing works
Konits, P. H., Egorin, M. J., Echo, D. A. V., et al. (1982) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00255484 · Cited by 23 · see citing works
Geographic Heterogeneity for Mismatch Repair Proteins Is Associated with Defects in DNA Repair.
Greenberg, A., Kariv, R., Solar, I., et al. (2020) · PubMed · Cited by 11 · see citing works
Chen, L., Yan, H.-X., Liu, X., et al. (2020) · Medicine · doi:10.1097/md.0000000000020082 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Current and emerging concepts for systemic treatment of metastatic colorectal cancer
Steup, C., Kennel, K. B., Neurath, M. F., Fichtner-Feigl, S., & Greten, F. R. (2025) · Gut · doi:10.1136/gutjnl-2025-335412 · Cited by 39 · see citing works
- Authors
- Amodio, V., Lamba, S., Chilà, R., Cattaneo, C. M., Mussolin, B., Corti, G., Rospo, G., Berrino, E., Tripodo, C., Pisati, F., Bartolini, A., Aquilano, M. C., Marsoni, S., Mauri, G., Marchiò, C., Abrignani, S., Di Nicolantonio, F., Germano, G., & Bardelli, A.
- Affiliations
- Candiolo Cancer Institute (IT)
- IFOM (IT)
- Cogentech S.R.L. Società Benefit a Socio Unico soggetta all’attività di direzione e coordinamento di IFOM - Istituto Fondazione di Oncologia Molecolare ETS (Italy) (IT)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- University of Milan (IT)
- Corresponding author
- Germano, Giovanni
- Bardelli, Alberto
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 41
- Issue
- 1
- Pages
- 196-209.e5
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC9833846
- OpenAlex
- W4313266792
- Cited by
- 39
- References
- 45
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 10 · 2023: 8
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by-nc-nd)
- IRIS UniPA (University of Palermo) (submittedVersion, cc-by-nc-nd)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, cc-by-nc-nd)
- Funders
- European Research Council
- Fundacion Cientifica de la Asociacion Espaoola Contra el Cancer
- Associazione Italiana per la Ricerca sul Cancro (22795)
- Università degli Studi di Torino
- Innovative Medicines Initiative (101007937 PERSIST-SEQ)
- Cancer Research UK
- Horizon 2020 Framework Programme (101020342)
- Fondazione Italiana per la Ricerca sul Cancro Airc
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- mismatch repair deficiency, colorectal cancer, tumor heterogeneity, immune surveillance, immune checkpoint blockade, MLH1, 6-thioguanine, tumor immunogenicity, tumor rejection
- MeSH terms
- Animals, Brain Neoplasms, Neoplastic Syndromes, Hereditary, Colorectal Neoplasms, Mice, Microsatellite Instability, DNA Mismatch Repair
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
