Journal Article
. 2021 Nov; 21(1):1222.
doi: 10.1186/s12885-021-08974-3.

Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response

Yosuke Sato 1 Yu Fu 2 Hong Liu 2 Min Young Lee 2 Michael H Shaw 2 
  • PMID: 34774008
  •     44 References
  •     1 citations


Background: Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response.

Methods: In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response.

Results: We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. Immune-profiling showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26. Genomic/transcriptomic analyses highlighted thatWnt pathway was one of the potential differences between CT-26 and Colon 26, showing Wnt activity was higher in Colon 26 than CT-26. .

Conclusions: CT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed "hot tumor" profile with more infiltrated immune cells than Colon 26. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients.

Keywords: Anti-PD-1; Anti-tumor activity; CT-26; Colon 26; Immune checkpoint blockade; Syngeneic model; Wnt.

Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance.
Young-Jun Park, Da-Sol Kuen, Yeonseok Chung.
Exp Mol Med, 2018 Aug 24; 50(8). PMID: 30135516    Free PMC article.
Highly Cited. Review.
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.
Jonathan E Rosenberg, Jean Hoffman-Censits, +28 authors, Robert Dreicer.
Lancet, 2016 Mar 10; 387(10031). PMID: 26952546    Free PMC article.
Highly Cited.
Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.
Celine Boutros, Ahmad Tarhini, +14 authors, Caroline Robert.
Nat Rev Clin Oncol, 2016 May 05; 13(8). PMID: 27141885
Highly Cited. Review.
Axon guidance and injury-lessons from Wnts and Wnt signaling.
Keisuke Onishi, Edmund Hollis, Yimin Zou.
Curr Opin Neurobiol, 2014 Jun 14; 27. PMID: 24927490    Free PMC article.
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.
Martin Reck, Delvys Rodríguez-Abreu, +16 authors, KEYNOTE-024 Investigators.
N Engl J Med, 2016 Oct 11; 375(19). PMID: 27718847
Highly Cited.
Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor.
H Nishio, T Yaguchi, +10 authors, Y Kawakami.
Br J Cancer, 2014 May 29; 110(12). PMID: 24867687    Free PMC article.
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.
Matthew D Hellmann, Tudor-Eliade Ciuleanu, +21 authors, Luis Paz-Ares.
N Engl J Med, 2018 Apr 17; 378(22). PMID: 29658845    Free PMC article.
Highly Cited.
Wnt Signaling and Colorectal Cancer.
Emma M Schatoff, Benjamin I Leach, Lukas E Dow.
Curr Colorectal Cancer Rep, 2017 Apr 18; 13(2). PMID: 28413363    Free PMC article.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy.
Nisha Nagarsheth, Max S Wicha, Weiping Zou.
Nat Rev Immunol, 2017 May 31; 17(9). PMID: 28555670    Free PMC article.
Highly Cited. Review.
Inhibitors of the PD-1 Pathway in Tumor Therapy.
Martin W LaFleur, Yuki Muroyama, Charles G Drake, Arlene H Sharpe.
J Immunol, 2018 Jan 10; 200(2). PMID: 29311378    Free PMC article.
Genetic basis for clinical response to CTLA-4 blockade in melanoma.
Alexandra Snyder, Vladimir Makarov, +18 authors, Timothy A Chan.
N Engl J Med, 2014 Nov 20; 371(23). PMID: 25409260    Free PMC article.
Highly Cited.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.
Robert J Motzer, Bernard Escudier, +25 authors, CheckMate 025 Investigators.
N Engl J Med, 2015 Sep 26; 373(19). PMID: 26406148    Free PMC article.
Highly Cited.
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
Nadeem Riaz, Jonathan J Havel, +22 authors, Timothy A Chan.
Cell, 2017 Oct 17; 171(4). PMID: 29033130    Free PMC article.
Highly Cited.
Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
Naiyer A Rizvi, Matthew D Hellmann, +21 authors, Timothy A Chan.
Science, 2015 Mar 15; 348(6230). PMID: 25765070    Free PMC article.
Highly Cited.
Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.
Eliezer M Van Allen, Diana Miao, +19 authors, Levi A Garraway.
Science, 2015 Sep 12; 350(6257). PMID: 26359337    Free PMC article.
Highly Cited.
Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors.
Diana Miao, Claire A Margolis, +28 authors, Eliezer M Van Allen.
Nat Genet, 2018 Aug 29; 50(9). PMID: 30150660    Free PMC article.
Highly Cited.
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.
Patrick M Forde, Jamie E Chaft, +32 authors, Drew M Pardoll.
N Engl J Med, 2018 Apr 17; 378(21). PMID: 29658848    Free PMC article.
Highly Cited.
A growing field: The regulation of axonal regeneration by Wnt signaling.
Armando L Garcia, Adanna Udeh, Karthik Kalahasty, Abigail S Hackam.
Neural Regen Res, 2018 Feb 17; 13(1). PMID: 29451203    Free PMC article.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982    Free PMC article.
Highly Cited.
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.
Willy Hugo, Jesse M Zaretsky, +15 authors, Roger S Lo.
Cell, 2016 Mar 22; 165(1). PMID: 26997480    Free PMC article.
Highly Cited.
Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.
Melissa G Lechner, Saman S Karimi, +6 authors, Alan L Epstein.
J Immunother, 2013 Oct 23; 36(9). PMID: 24145359    Free PMC article.
Highly Cited.
Novel targeting approaches and signaling pathways of colorectal cancer: An insight.
Ankita Tiwari, Shivani Saraf, +2 authors, Sanjay K Jain.
World J Gastroenterol, 2018 Oct 26; 24(39). PMID: 30357011    Free PMC article.
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy.
Spencer C Wei, Colm R Duffy, James P Allison.
Cancer Discov, 2018 Aug 18; 8(9). PMID: 30115704
Highly Cited. Review.
Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts.
Aimy Sebastian, Nicholas R Hum, +3 authors, Gabriela G Loots.
PLoS One, 2017 Nov 28; 12(11). PMID: 29176883    Free PMC article.
PD-1 blockade induces responses by inhibiting adaptive immune resistance.
Paul C Tumeh, Christina L Harview, +23 authors, Antoni Ribas.
Nature, 2014 Nov 28; 515(7528). PMID: 25428505    Free PMC article.
Highly Cited.
Emerging Roles of Wnt Ligands in Human Colorectal Cancer.
Xiaobo Nie, Huiyang Liu, +2 authors, Wei-Dong Chen.
Front Oncol, 2020 Sep 15; 10. PMID: 32923386    Free PMC article.
RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade.
Shanthi Ganesh, Xue Shui, +4 authors, Marc T Abrams.
Mol Ther, 2018 Oct 03; 26(11). PMID: 30274786    Free PMC article.
Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.
Samra Turajlic, Kevin Litchfield, +17 authors, Charles Swanton.
Lancet Oncol, 2017 Jul 12; 18(8). PMID: 28694034
Highly Cited.
The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells.
Hidetoshi Sumimoto, Fumie Imabayashi, Tomoko Iwata, Yutaka Kawakami.
J Exp Med, 2006 Jun 28; 203(7). PMID: 16801397    Free PMC article.
Highly Cited.
Enhanced cancer immunotherapy using STAT3-depleted dendritic cells with high Th1-inducing ability and resistance to cancer cell-derived inhibitory factors.
Tomoko Iwata-Kajihara, Hidetoshi Sumimoto, +6 authors, Yutaka Kawakami.
J Immunol, 2011 Jun 03; 187(1). PMID: 21632716
Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells.
Tomonori Yaguchi, Yasufumi Goto, +7 authors, Yutaka Kawakami.
J Immunol, 2012 Jul 21; 189(5). PMID: 22815287
Approaches to treat immune hot, altered and cold tumours with combination immunotherapies.
Jérôme Galon, Daniela Bruni.
Nat Rev Drug Discov, 2019 Jan 06; 18(3). PMID: 30610226
Highly Cited. Review.
Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.
Matthew D Hellmann, Tavi Nathanson, +29 authors, Jedd D Wolchok.
Cancer Cell, 2018 Apr 17; 33(5). PMID: 29657128    Free PMC article.
Highly Cited.
WNT Signaling in Cancer Immunosurveillance.
Lorenzo Galluzzi, Stefani Spranger, Elaine Fuchs, Alejandro López-Soto.
Trends Cell Biol, 2018 Sep 18; 29(1). PMID: 30220580    Free PMC article.
Highly Cited. Review.
Tumor Mutational Burden and Response Rate to PD-1 Inhibition.
Mark Yarchoan, Alexander Hopkins, Elizabeth M Jaffee.
N Engl J Med, 2017 Dec 21; 377(25). PMID: 29262275    Free PMC article.
Highly Cited.
Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference.
Hidetoshi Sumimoto, Makoto Miyagishi, +4 authors, Yutaka Kawakami.
Oncogene, 2004 Jun 23; 23(36). PMID: 15208655
Effects of Wnt3A and mechanical load on cartilage chondrocyte homeostasis.
Rhian S Thomas, Alan R Clarke, Victor C Duance, Emma J Blain.
Arthritis Res Ther, 2011 Dec 14; 13(6). PMID: 22151902    Free PMC article.
CTLA-4 is a direct target of Wnt/beta-catenin signaling and is expressed in human melanoma tumors.
Kavita V Shah, Andy J Chien, Cassian Yee, Randall T Moon.
J Invest Dermatol, 2008 Jun 20; 128(12). PMID: 18563180    Free PMC article.
Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer.
Matthew D Hellmann, Margaret K Callahan, +13 authors, Scott J Antonia.
Cancer Cell, 2018 May 08; 33(5). PMID: 29731394    Free PMC article.
Highly Cited.
Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.
Aaron M Goodman, Shumei Kato, +6 authors, Razelle Kurzrock.
Mol Cancer Ther, 2017 Aug 25; 16(11). PMID: 28835386    Free PMC article.
Highly Cited.
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy.
Jonathan J Havel, Diego Chowell, Timothy A Chan.
Nat Rev Cancer, 2019 Feb 14; 19(3). PMID: 30755690    Free PMC article.
Highly Cited. Review.
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.
Stefani Spranger, Riyue Bao, Thomas F Gajewski.
Nature, 2015 May 15; 523(7559). PMID: 25970248
Highly Cited.
Wnt signaling in axon guidance.
Yimin Zou.
Trends Neurosci, 2004 Aug 28; 27(9). PMID: 15331234
Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response.
Tristan Rupp, Laurie Genest, +4 authors, Vincent Castagné.
Transl Oncol, 2022 Mar 28; 20. PMID: 35339889    Free PMC article.