Wnt/β-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers
Abstract
:1. Introduction
2. Wnt Pathways in Cancer
2.1. Canonical Wnt Pathway
2.2. Non-Canonical Wnt Pathways
2.3. The Wnt/β-Catenin Pathway and Cancer
3. The Wnt/β-Catenin Pathway Is a Tumor-Intrinsic Mechanism of Resistance to Immune Checkpoint Inhibitors
3.1. Tumor-Intrinsic Mechanisms of Immune-Checkpoint-Inhibitor Resistance
3.2. Wnt/β-Catenin Induces T-Cell Exclusion
3.3. The Wnt/β-Catenin Pathway and Immunoediting in Cancer
4. Overcoming Immune-Checkpoint-Inhibitor Resistance with Wnt/β-Catenin Signaling
4.1. Combination Therapy with Chemotherapy and Immune Checkpoint Inhibitors
4.2. Neoadjuvant Treatment Strategies
4.3. Combination Therapy with Inhibitors of Wnt/β-Catenin Signaling and Immune Checkpoint Inhibitors
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Goldstraw, P.; Chansky, K.; Crowley, J.; Rami-Porta, R.; Asamura, H.; Eberhardt, W.E.E.; Nicholson, A.G.; Groome, P.; Mitchell, A.; Bolejack, V.; et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 2016, 11, 39–51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kris, M.G.; Johnson, B.E.; Berry, L.D.; Kwiatkowski, D.J.; Iafrate, A.J.; Wistuba, I.I.; Varella-Garcia, M.; Franklin, W.A.; Aronson, S.L.; Su, P.F.; et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014, 311, 1998–2006. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Borghaei, H.; Gettinger, S.; Vokes, E.E.; Chow, L.Q.M.; Burgio, M.A.; de Castro Carpeno, J.; Pluzanski, A.; Arrieta, O.; Frontera, O.A.; Chiari, R.; et al. Five-Year Outcomes from the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer. J. Clin. Oncol. 2021, 39, 723–733. [Google Scholar] [CrossRef]
- Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2016, 375, 1823–1833. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mok, T.S.K.; Wu, Y.-L.; Kudaba, I.; Kowalski, D.M.; Cho, B.C.; Turna, H.Z.; Castro, G., Jr.; Srimuninnimit, V.; Laktionov, K.K.; Bondarenko, I.; et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 2019, 393, 1819–1830. [Google Scholar] [CrossRef] [PubMed]
- Rittmeyer, A.; Barlesi, F.; Waterkamp, D.; Park, K.; Ciardiello, F.; von Pawel, J.; Gadgeel, S.M.; Hida, T.; Kowalski, D.M.; Dols, M.C.; et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2017, 389, 255–265. [Google Scholar] [CrossRef]
- Herbst, R.S.; Giaccone, G.; de Marinis, F.; Reinmuth, N.; Vergnenegre, A.; Barrios, C.H.; Morise, M.; Felip, E.; Andric, Z.; Geater, S.; et al. Atezolizumab for First-Line Treatment of PD-L1–Selected Patients with NSCLC. N. Engl. J. Med. 2020, 383, 1328–1339. [Google Scholar] [CrossRef]
- Gandhi, L.; Rodriguez-Abreu, D.; Gadgeel, S.; Esteban, E.; Felip, E.; De Angelis, F.; Domine, M.; Clingan, P.; Hochmair, M.J.; Powell, S.F.; et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 378, 2078–2092. [Google Scholar] [CrossRef]
- Paz-Ares, L.; Luft, A.; Vicente, D.; Tafreshi, A.; Gümüş, M.; Mazières, J.; Hermes, B.; Çay Şenler, F.; Csőszi, T.; Fülöp, A.; et al. Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2040–2051. [Google Scholar] [CrossRef]
- Socinski, M.A.; Jotte, R.M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodríguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C.A.; Barlesi, F.; et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N. Engl. J. Med. 2018, 378, 2288–2301. [Google Scholar] [CrossRef] [PubMed]
- West, H.; McCleod, M.; Hussein, M.; Morabito, A.; Rittmeyer, A.; Conter, H.J.; Kopp, H.-G.; Daniel, D.; McCune, S.; Mekhail, T.; et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019, 20, 924–937. [Google Scholar] [CrossRef] [PubMed]
- Nishio, M.; Barlesi, F.; West, H.; Ball, S.; Bordoni, R.; Cobo, M.; Longeras, P.D.; Goldschmidt, J., Jr.; Novello, S.; Orlandi, F.; et al. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results from the Randomized Phase 3 IMpower132 Trial. J. Thorac. Oncol. 2021, 16, 653–664. [Google Scholar] [CrossRef] [PubMed]
- Hellmann, M.D.; Paz-Ares, L.; Bernabe Caro, R.; Zurawski, B.; Kim, S.-W.; Carcereny Costa, E.; Park, K.; Alexandru, A.; Lupinacci, L.; de la Mora Jimenez, E.; et al. Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2019, 381, 2020–2031. [Google Scholar] [CrossRef]
- Paz-Ares, L.; Ciuleanu, T.-E.; Cobo, M.; Schenker, M.; Zurawski, B.; Menezes, J.; Richardet, E.; Bennouna, J.; Felip, E.; Juan-Vidal, O.; et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): An international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021, 22, 198–211. [Google Scholar] [CrossRef] [PubMed]
- Johnson, M.L.; Cho, B.C.; Luft, A.; Alatorre-Alexander, J.; Geater, S.L.; Laktionov, K.; Kim, S.-W.; Ursol, G.; Hussein, M.; Lim, F.L.; et al. Durvalumab with or without Tremelimumab in Combination with Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study. J. Clin. Oncol. 2022; ahead of print. [Google Scholar] [CrossRef]
- Spranger, S.; Bao, R.; Gajewski, T.F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015, 523, 231–235. [Google Scholar] [CrossRef] [PubMed]
- Pai, S.G.; Carneiro, B.A.; Mota, J.M.; Costa, R.; Leite, C.A.; Barroso-Sousa, R.; Kaplan, J.B.; Chae, Y.K.; Giles, F.J. Wnt/beta-catenin pathway: Modulating anticancer immune response. J. Hematol. Oncol. 2017, 10, 101. [Google Scholar] [CrossRef] [Green Version]
- Galluzzi, L.; Spranger, S.; Fuchs, E.; López-Soto, A. WNT Signaling in Cancer Immunosurveillance. Trends Cell Biol. 2019, 29, 44–65. [Google Scholar] [CrossRef]
- Spranger, S.; Gajewski, T.F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 2018, 18, 139–147. [Google Scholar] [CrossRef]
- Kalbasi, A.; Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 2020, 20, 25–39. [Google Scholar] [CrossRef]
- Goldsberry, W.N.; Londoño, A.; Randall, T.D.; Norian, L.A.; Arend, R.C. A Review of the Role of Wnt in Cancer Immunomodulation. Cancers 2019, 11, 771. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nusse, R.; Varmus, H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982, 31, 99–109. [Google Scholar] [CrossRef] [PubMed]
- Kim, W.; Kim, M.; Jho, E.-h. Wnt/β-catenin signalling: From plasma membrane to nucleus. Biochem. J. 2013, 450, 9–21. [Google Scholar] [CrossRef] [PubMed]
- Staal, F.J.; Luis, T.C.; Tiemessen, M.M. WNT signalling in the immune system: WNT is spreading its wings. Nat. Rev. Immunol. 2008, 8, 581–593. [Google Scholar] [CrossRef] [PubMed]
- Gattinoni, L.; Ji, Y.; Restifo, N.P. Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy. Clin. Cancer Res. 2010, 16, 4695–4701. [Google Scholar] [CrossRef] [Green Version]
- Kusserow, A.; Pang, K.; Sturm, C.; Hrouda, M.; Lentfer, J.; Schmidt, H.A.; Technau, U.; von Haeseler, A.; Hobmayer, B.; Martindale, M.Q.; et al. Unexpected complexity of the Wnt gene family in a sea anemone. Nature 2005, 433, 156–160. [Google Scholar] [CrossRef]
- Du, S.J.; Purcell, S.M.; Christian, J.L.; McGrew, L.L.; Moon, R.T. Identification of distinct classes and functional domains of Wnts through expression of wild-type and chimeric proteins in Xenopus embryos. Mol. Cell Biol. 1995, 15, 2625–2634. [Google Scholar] [CrossRef] [Green Version]
- Nusse, R.; Clevers, H. Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell 2017, 169, 985–999. [Google Scholar] [CrossRef] [Green Version]
- Masuda, T.; Ishitani, T. Context-dependent regulation of the β-catenin transcriptional complex supports diverse functions of Wnt/β-catenin signaling. J. Biochem. 2017, 161, 9–17. [Google Scholar] [CrossRef]
- Pate, K.T.; Stringari, C.; Sprowl-Tanio, S.; Wang, K.; TeSlaa, T.; Hoverter, N.P.; McQuade, M.M.; Garner, C.; Digman, M.A.; Teitell, M.A.; et al. Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J. 2014, 33, 1454–1473. [Google Scholar] [CrossRef] [Green Version]
- Yeung, S.J.; Pan, J.; Lee, M.H. Roles of p53, MYC and HIF-1 in regulating glycolysis—The seventh hallmark of cancer. Cell Mol. Life Sci. 2008, 65, 3981–3999. [Google Scholar] [CrossRef] [PubMed]
- Wise, D.R.; DeBerardinis, R.J.; Mancuso, A.; Sayed, N.; Zhang, X.Y.; Pfeiffer, H.K.; Nissim, I.; Daikhin, E.; Yudkoff, M.; McMahon, S.B.; et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. USA 2008, 105, 18782–18787. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, H.; Li, Z.; Yang, P.; Zhang, L.; Fan, Y.; Li, Z. PKM2 depletion induces the compensation of glutaminolysis through β-catenin/c-Myc pathway in tumor cells. Cell. Signal. 2014, 26, 2397–2405. [Google Scholar] [CrossRef]
- Corda, G.; Sala, A. Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage. Oncogenesis 2017, 6, e364. [Google Scholar] [CrossRef] [Green Version]
- Katoh, M. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review). Int. J. Oncol. 2017, 51, 1357–1369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, S.; Chen, L.; Cui, B.; Chuang, H.-Y.; Yu, J.; Wang-Rodriguez, J.; Tang, L.; Chen, G.; Basak, G.W.; Kipps, T.J. ROR1 Is Expressed in Human Breast Cancer and Associated with Enhanced Tumor-Cell Growth. PLoS ONE 2012, 7, e31127. [Google Scholar] [CrossRef] [Green Version]
- De, A. Wnt/Ca2+ signaling pathway: A brief overview. Acta Biochim. Biophys. Sin. 2011, 43, 745. [Google Scholar] [CrossRef]
- Rijsewijk, F.; van Deemter, L.; Wagenaar, E.; Sonnenberg, A.; Nusse, R. Transfection of the int-1 mammary oncogene in cuboidal RAC mammary cell line results in morphological transformation and tumorigenicity. EMBO J. 1987, 6, 127–131. [Google Scholar] [CrossRef]
- Morin, P.J.; Sparks, A.B.; Korinek, V.; Barker, N.; Clevers, H.; Vogelstein, B.; Kinzler, K.W. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997, 275, 1787–1790. [Google Scholar] [CrossRef]
- Rubinfeld, B.; Robbins, P.; El-Gamil, M.; Albert, I.; Porfiri, E.; Polakis, P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275, 1790–1792. [Google Scholar] [CrossRef]
- Nishisho, I.; Nakamura, Y.; Miyoshi, Y.; Miki, Y.; Ando, H.; Horii, A.; Koyama, K.; Utsunomiya, J.; Baba, S.; Hedge, P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991, 253, 665–669. [Google Scholar] [CrossRef]
- Yaeger, R.; Chatila, W.K.; Lipsyc, M.D.; Hechtman, J.F.; Cercek, A.; Sanchez-Vega, F.; Jayakumaran, G.; Middha, S.; Zehir, A.; Donoghue, M.T.A.; et al. Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer. Cancer Cell 2018, 33, 125–136.e3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Satoh, S.; Daigo, Y.; Furukawa, Y.; Kato, T.; Miwa, N.; Nishiwaki, T.; Kawasoe, T.; Ishiguro, H.; Fujita, M.; Tokino, T.; et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 2000, 24, 245–250. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.; Dong, X.; Mai, M.; Seelan, R.S.; Taniguchi, K.; Krishnadath, K.K.; Halling, K.C.; Cunningham, J.M.; Boardman, L.A.; Qian, C.; et al. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat. Genet. 2000, 26, 146–147. [Google Scholar] [CrossRef] [PubMed]
- Guezguez, B.; Almakadi, M.; Benoit, Y.D.; Shapovalova, Z.; Rahmig, S.; Fiebig-Comyn, A.; Casado, F.L.; Tanasijevic, B.; Bresolin, S.; Masetti, R.; et al. GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia. Cancer Cell 2016, 29, 61–74. [Google Scholar] [CrossRef] [Green Version]
- Kim, Y.; Jin, D.; Lee, B.B.; Cho, E.Y.; Han, J.; Shim, Y.M.; Kim, H.K.; Kim, D.-H. Overexpression of β-Catenin and Cyclin D1 is Associated with Poor Overall Survival in Patients with Stage IA–IIA Squamous Cell Lung Cancer Irrespective of Adjuvant Chemotherapy. J. Thorac. Oncol. 2016, 11, 2193–2201. [Google Scholar] [CrossRef]
- Bodnar, L.; Stanczak, A.; Cierniak, S.; Smoter, M.; Cichowicz, M.; Kozlowski, W.; Szczylik, C.; Wieczorek, M.; Lamparska-Przybysz, M. Wnt/β-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer. J. Ovarian Res. 2014, 7, 16. [Google Scholar] [CrossRef] [Green Version]
- Godwin, A.K.; Meister, A.; O’Dwyer, P.J.; Huang, C.S.; Hamilton, T.C.; Anderson, M.E. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc. Natl. Acad. Sci. USA 1992, 89, 3070–3074. [Google Scholar] [CrossRef] [Green Version]
- Ishimoto, T.; Nagano, O.; Yae, T.; Tamada, M.; Motohara, T.; Oshima, H.; Oshima, M.; Ikeda, T.; Asaba, R.; Yagi, H.; et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 2011, 19, 387–400. [Google Scholar] [CrossRef]
- Wang, H.; Zhang, G.; Zhang, H.; Zhang, F.; Zhou, B.; Ning, F.; Wang, H.-S.; Cai, S.-H.; Du, J. Acquisition of epithelial–mesenchymal transition phenotype and cancer stem cell-like properties in cisplatin-resistant lung cancer cells through AKT/β-catenin/Snail signaling pathway. Eur. J. Pharmacol. 2014, 723, 156–166. [Google Scholar] [CrossRef]
- Chen, D.S.; Mellman, I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 2013, 39, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ott, P.A.; Hu, Z.; Keskin, D.B.; Shukla, S.A.; Sun, J.; Bozym, D.J.; Zhang, W.; Luoma, A.; Giobbie-Hurder, A.; Peter, L.; et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017, 547, 217–221. [Google Scholar] [CrossRef] [Green Version]
- Yarchoan, M.; Hopkins, A.; Jaffee, E.M. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N. Engl. J. Med. 2017, 377, 2500–2501. [Google Scholar] [CrossRef] [PubMed]
- Le, D.T.; Kim, T.W.; Van Cutsem, E.; Geva, R.; Jäger, D.; Hara, H.; Burge, M.; O’Neil, B.; Kavan, P.; Yoshino, T.; et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J. Clin. Oncol. 2020, 38, 11–19. [Google Scholar] [CrossRef]
- Marabelle, A.; Le, D.T.; Ascierto, P.A.; Di Giacomo, A.M.; De Jesus-Acosta, A.; Delord, J.P.; Geva, R.; Gottfried, M.; Penel, N.; Hansen, A.R.; et al. Efficacy of Pembrolizumab in Patients with Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J. Clin. Oncol. 2020, 38, 1–10. [Google Scholar] [CrossRef]
- Menon, A.G.; Morreau, H.; Tollenaar, R.A.E.M.; Alphenaar, E.; van Puijenbroek, M.; Putter, H.; Janssen-van Rhijn, C.M.; van de Velde, C.J.H.; Fleuren, G.J.; Kuppen, P.J.K. Down-Regulation of HLA-A Expression Correlates with a Better Prognosis in Colorectal Cancer Patients. Lab. Investig. 2002, 82, 1725–1733. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kloor, M.; Becker, C.; Benner, A.; Woerner, S.M.; Gebert, J.; Ferrone, S.; von Knebel Doeberitz, M. Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers. Cancer Res. 2005, 65, 6418–6424. [Google Scholar] [CrossRef] [Green Version]
- Meissner, M.; Reichert, T.E.; Kunkel, M.; Gooding, W.; Whiteside, T.L.; Ferrone, S.; Seliger, B. Defects in the Human Leukocyte Antigen Class I Antigen Processing Machinery in Head and Neck Squamous Cell Carcinoma: Association with Clinical Outcome. Clin. Cancer Res. 2005, 11, 2552–2560. [Google Scholar] [CrossRef] [Green Version]
- Sucker, A.; Zhao, F.; Real, B.; Heeke, C.; Bielefeld, N.; Maβen, S.; Horn, S.; Moll, I.; Maltaner, R.; Horn, P.A.; et al. Genetic evolution of T-cell resistance in the course of melanoma progression. Clin. Cancer Res. 2014, 20, 6593–6604. [Google Scholar] [CrossRef]
- McGranahan, N.; Rosenthal, R.; Hiley, C.T.; Rowan, A.J.; Watkins, T.B.K.; Wilson, G.A.; Birkbak, N.J.; Veeriah, S.; Van Loo, P.; Herrero, J.; et al. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. Cell 2017, 171, 1259–1271.e11. [Google Scholar] [CrossRef] [Green Version]
- Montesion, M.; Murugesan, K.; Jin, D.X.; Sharaf, R.; Sanchez, N.; Guria, A.; Minker, M.; Li, G.; Fisher, V.; Sokol, E.S.; et al. Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response. Cancer Discov. 2021, 11, 282–292. [Google Scholar] [CrossRef] [PubMed]
- 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. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N. Engl. J. Med. 2016, 375, 819–829. [Google Scholar] [CrossRef] [PubMed]
- Gao, J.; Shi, L.Z.; Zhao, H.; Chen, J.; Xiong, L.; He, Q.; Chen, T.; Roszik, J.; Bernatchez, C.; Woodman, S.E.; et al. Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy. Cell 2016, 167, 397–404.e9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sucker, A.; Zhao, F.; Pieper, N.; Heeke, C.; Maltaner, R.; Stadtler, N.; Real, B.; Bielefeld, N.; Howe, S.; Weide, B.; et al. Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nat. Commun. 2017, 8, 15440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Horn, S.; Leonardelli, S.; Sucker, A.; Schadendorf, D.; Griewank, K.G.; Paschen, A. Tumor CDKN2A-Associated JAK2 Loss and Susceptibility to Immunotherapy Resistance. J. Natl. Cancer Inst. 2018, 110, 677–681. [Google Scholar] [CrossRef]
- Manguso, R.T.; Pope, H.W.; Zimmer, M.D.; Brown, F.D.; Yates, K.B.; Miller, B.C.; Collins, N.B.; Bi, K.; LaFleur, M.W.; Juneja, V.R.; et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 2017, 547, 413–418. [Google Scholar] [CrossRef] [Green Version]
- Patel, S.J.; Sanjana, N.E.; Kishton, R.J.; Eidizadeh, A.; Vodnala, S.K.; Cam, M.; Gartner, J.J.; Jia, L.; Steinberg, S.M.; Yamamoto, T.N.; et al. Identification of essential genes for cancer immunotherapy. Nature 2017, 548, 537–542. [Google Scholar] [CrossRef] [Green Version]
- Pan, D.; Kobayashi, A.; Jiang, P.; Ferrari de Andrade, L.; Tay, R.E.; Luoma, A.M.; Tsoucas, D.; Qiu, X.; Lim, K.; Rao, P.; et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 2018, 359, 770–775. [Google Scholar] [CrossRef] [Green Version]
- Han, P.; Dai, Q.; Fan, L.; Lin, H.; Zhang, X.; Li, F.; Yang, X. Genome-Wide CRISPR Screening Identifies JAK1 Deficiency as a Mechanism of T-Cell Resistance. Front. Immunol. 2019, 10, 251. [Google Scholar] [CrossRef]
- Cha, Y.J.; Kim, H.R.; Lee, C.Y.; Cho, B.C.; Shim, H.S. Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status. Lung Cancer 2016, 97, 73–80. [Google Scholar] [CrossRef]
- Akbay, E.A.; Koyama, S.; Carretero, J.; Altabef, A.; Tchaicha, J.H.; Christensen, C.L.; Mikse, O.R.; Cherniack, A.D.; Beauchamp, E.M.; Pugh, T.J.; et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013, 3, 1355–1363. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Borghaei, H.; Paz-Ares, L.; Horn, L.; Spigel, D.R.; Steins, M.; Ready, N.E.; Chow, L.Q.; Vokes, E.E.; Felip, E.; Holgado, E.; et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2015, 373, 1627–1639. [Google Scholar] [CrossRef] [PubMed]
- Busch, S.E.; Hanke, M.L.; Kargl, J.; Metz, H.E.; MacPherson, D.; Houghton, A.M. Lung Cancer Subtypes Generate Unique Immune Responses. J. Immunol. 2016, 197, 4493–4503. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sugiyama, E.; Togashi, Y.; Takeuchi, Y.; Shinya, S.; Tada, Y.; Kataoka, K.; Tane, K.; Sato, E.; Ishii, G.; Goto, K.; et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non–small cell lung cancer. Sci. Immunol. 2020, 5, eaav3937. [Google Scholar] [CrossRef]
- Kumagai, S.; Togashi, Y.; Kamada, T.; Sugiyama, E.; Nishinakamura, H.; Takeuchi, Y.; Vitaly, K.; Itahashi, K.; Maeda, Y.; Matsui, S.; et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat. Immunol. 2020, 21, 1346–1358. [Google Scholar] [CrossRef]
- Ferrara, R.; Mezquita, L.; Texier, M.; Lahmar, J.; Audigier-Valette, C.; Tessonnier, L.; Mazieres, J.; Zalcman, G.; Brosseau, S.; Le Moulec, S.; et al. Hyperprogressive Disease in Patients with Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy. JAMA Oncol. 2018, 4, 1543–1552. [Google Scholar] [CrossRef]
- Oxnard, G.R.; Yang, J.C.; Yu, H.; Kim, S.W.; Saka, H.; Horn, L.; Goto, K.; Ohe, Y.; Mann, H.; Thress, K.S.; et al. TATTON: A multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann. Oncol. 2020, 31, 507–516. [Google Scholar] [CrossRef] [Green Version]
- Pereira, F.; Ferreira, A.; Reis, C.A.; Sousa, M.J.; Oliveira, M.J.; Preto, A. KRAS as a Modulator of the Inflammatory Tumor Microenvironment: Therapeutic Implications. Cells 2022, 11, 398. [Google Scholar] [CrossRef]
- Kortlever, R.M.; Sodir, N.M.; Wilson, C.H.; Burkhart, D.L.; Pellegrinet, L.; Brown Swigart, L.; Littlewood, T.D.; Evan, G.I. Myc Cooperates with Ras by Programming Inflammation and Immune Suppression. Cell 2017, 171, 1301–1315.e14. [Google Scholar] [CrossRef]
- Kumagai, S.; Koyama, S.; Itahashi, K.; Tanegashima, T.; Lin, Y.T.; Togashi, Y.; Kamada, T.; Irie, T.; Okumura, G.; Kono, H.; et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022, 40, 201–218.e9. [Google Scholar] [CrossRef]
- Pinyol, R.; Sia, D.; Llovet, J.M. Immune Exclusion-Wnt/CTNNB1 Class Predicts Resistance to Immunotherapies in HCC. Clin. Cancer Res. 2019, 25, 2021–2023. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Koyama, S.; Akbay, E.A.; Li, Y.Y.; Aref, A.R.; Skoulidis, F.; Herter-Sprie, G.S.; Buczkowski, K.A.; Liu, Y.; Awad, M.M.; Denning, W.L.; et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 2016, 76, 999–1008. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Skoulidis, F.; Goldberg, M.E.; Greenawalt, D.M.; Hellmann, M.D.; Awad, M.M.; Gainor, J.F.; Schrock, A.B.; Hartmaier, R.J.; Trabucco, S.E.; Gay, L.; et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov. 2018, 8, 822–835. [Google Scholar] [CrossRef] [Green Version]
- Wellenstein, M.D.; de Visser, K.E. Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape. Immunity 2018, 48, 399–416. [Google Scholar] [CrossRef] [Green Version]
- Spranger, S.; Dai, D.; Horton, B.; Gajewski, T.F. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell 2017, 31, 711–723.e4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grasso, C.S.; Giannakis, M.; Wells, D.K.; Hamada, T.; Mu, X.J.; Quist, M.; Nowak, J.A.; Nishihara, R.; Qian, Z.R.; Inamura, K.; et al. Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov. 2018, 8, 730–749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Seiwert, T.Y.; Zuo, Z.; Keck, M.K.; Khattri, A.; Pedamallu, C.S.; Stricker, T.; Brown, C.; Pugh, T.J.; Stojanov, P.; Cho, J.; et al. Integrative and Comparative Genomic Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas. Clin. Cancer Res. 2015, 21, 632–641. [Google Scholar] [CrossRef] [Green Version]
- Sweis, R.F.; Spranger, S.; Bao, R.; Paner, G.P.; Stadler, W.M.; Steinberg, G.; Gajewski, T.F. Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer. Cancer Immunol. Res. 2016, 4, 563–568. [Google Scholar] [CrossRef] [Green Version]
- Sridharan, V.; Gjini, E.; Liao, X.; Chau, N.G.; Haddad, R.I.; Severgnini, M.; Hammerman, P.; El-Naggar, A.; Freeman, G.J.; Hodi, F.S.; et al. Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes. Cancer Immunol. Res. 2016, 4, 679–687. [Google Scholar] [CrossRef]
- Jiménez-Sánchez, A.; Memon, D.; Pourpe, S.; Veeraraghavan, H.; Li, Y.; Vargas, H.A.; Gill, M.B.; Park, K.J.; Zivanovic, O.; Konner, J.; et al. Heterogeneous Tumor-Immune Microenvironments among Differentially Growing Metastases in an Ovarian Cancer Patient. Cell 2017, 170, 927–938.e20. [Google Scholar] [CrossRef] [Green Version]
- Muto, S.; Ozaki, Y.; Yamaguchi, H.; Mine, H.; Takagi, H.; Watanabe, M.; Inoue, T.; Yamaura, T.; Fukuhara, M.; Okabe, N.; et al. Tumor β-catenin expression is associated with immune evasion in non-small cell lung cancer with high tumor mutation burden. Oncol. Lett. 2021, 21, 203. [Google Scholar] [CrossRef] [PubMed]
- Takeuchi, Y.; Tanegashima, T.; Sato, E.; Irie, T.; Sai, A.; Itahashi, K.; Kumagai, S.; Tada, Y.; Togashi, Y.; Koyama, S.; et al. Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape. Sci. Immunol. 2021, 6, eabc6424. [Google Scholar] [CrossRef] [PubMed]
- Robbins, P.F.; El-Gamil, M.; Li, Y.F.; Kawakami, Y.; Loftus, D.; Appella, E.; Rosenberg, S.A. A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 1996, 183, 1185–1192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DeNardo, D.G.; Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 2019, 19, 369–382. [Google Scholar] [CrossRef] [PubMed]
- Kaler, P.; Augenlicht, L.; Klampfer, L. Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: A crosstalk interrupted by vitamin D3. Oncogene 2009, 28, 3892–3902. [Google Scholar] [CrossRef] [Green Version]
- Kaler, P.; Augenlicht, L.; Klampfer, L. Activating Mutations in β-Catenin in Colon Cancer Cells Alter Their Interaction with Macrophages; the Role of Snail. PLoS ONE 2012, 7, e45462. [Google Scholar] [CrossRef]
- Hong, Y.; Manoharan, I.; Suryawanshi, A.; Majumdar, T.; Angus-Hill, M.L.; Koni, P.A.; Manicassamy, B.; Mellor, A.L.; Munn, D.H.; Manicassamy, S. β-Catenin Promotes Regulatory T-cell Responses in Tumors by Inducing Vitamin A Metabolism in Dendritic Cells. Cancer Res. 2015, 75, 656–665. [Google Scholar] [CrossRef] [Green Version]
- Van Loosdregt, J.; Fleskens, V.; Tiemessen, M.M.; Mokry, M.; van Boxtel, R.; Meerding, J.; Pals, C.E.; Kurek, D.; Baert, M.R.; Delemarre, E.M.; et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity 2013, 39, 298–310. [Google Scholar] [CrossRef] [Green Version]
- Yaguchi, T.; Goto, Y.; Kido, K.; Mochimaru, H.; Sakurai, T.; Tsukamoto, N.; Kudo-Saito, C.; Fujita, T.; Sumimoto, H.; Kawakami, Y. Immune Suppression and Resistance Mediated by Constitutive Activation of Wnt/β-Catenin Signaling in Human Melanoma Cells. J. Immunol. 2012, 189, 2110. [Google Scholar] [CrossRef]
- Pavlova, N.N.; Thompson, C.B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016, 23, 27–47. [Google Scholar] [CrossRef] [Green Version]
- Lim, A.R.; Rathmell, W.K.; Rathmell, J.C. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. eLife 2020, 9, e55185. [Google Scholar] [CrossRef] [PubMed]
- Harel, M.; Ortenberg, R.; Varanasi, S.K.; Mangalhara, K.C.; Mardamshina, M.; Markovits, E.; Baruch, E.N.; Tripple, V.; Arama-Chayoth, M.; Greenberg, E.; et al. Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence. Cell 2019, 179, 236–250.e18. [Google Scholar] [CrossRef] [PubMed]
- Bracci, L.; Schiavoni, G.; Sistigu, A.; Belardelli, F. Immune-based mechanisms of cytotoxic chemotherapy: Implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014, 21, 15–25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Z.; Till, B.; Gao, Q. Chemotherapeutic agent-mediated elimination of myeloid-derived suppressor cells. Oncoimmunology 2017, 6, e1331807. [Google Scholar] [CrossRef] [Green Version]
- Roselli, M.; Cereda, V.; di Bari, M.G.; Formica, V.; Spila, A.; Jochems, C.; Farsaci, B.; Donahue, R.; Gulley, J.L.; Schlom, J.; et al. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology 2013, 2, e27025. [Google Scholar] [CrossRef] [Green Version]
- Kalbasi, A.; June, C.H.; Haas, N.; Vapiwala, N. Radiation and immunotherapy: A synergistic combination. J. Clin. Investig. 2013, 123, 2756–2763. [Google Scholar] [CrossRef]
- Kroemer, G.; Galluzzi, L.; Kepp, O.; Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 2013, 31, 51–72. [Google Scholar] [CrossRef]
- Daguenet, E.; Louati, S.; Wozny, A.S.; Vial, N.; Gras, M.; Guy, J.B.; Vallard, A.; Rodriguez-Lafrasse, C.; Magné, N. Radiation-induced bystander and abscopal effects: Important lessons from preclinical models. Br. J. Cancer 2020, 123, 339–348. [Google Scholar] [CrossRef]
- De Castro, G.; Kudaba, I.; Wu, Y.-L.; Lopes, G.; Kowalski, D.M.; Turna, H.Z.; Caglevic, C.; Zhang, L.; Karaszewska, B.; Laktionov, K.K.; et al. Five-Year Outcomes with Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients with Non–Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study. J. Clin. Oncol. 2022; ahead of print. [Google Scholar] [CrossRef]
- Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Five-Year Outcomes with Pembrolizumab Versus Chemotherapy for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥50%. J. Clin. Oncol. 2021, 39, 2339–2349. [Google Scholar] [CrossRef]
- Rodríguez-Abreu, D.; Powell, S.F.; Hochmair, M.J.; Gadgeel, S.; Esteban, E.; Felip, E.; Speranza, G.; De Angelis, F.; Dómine, M.; Cheng, S.Y.; et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: Protocol-specified final analysis from KEYNOTE-189. Ann. Oncol. 2021, 32, 881–895. [Google Scholar] [CrossRef]
- West, H.J.; McCleland, M.; Cappuzzo, F.; Reck, M.; Mok, T.S.K.; Jotte, R.M.; Nishio, M.; Kim, E.; Morris, S.; Zou, W.; et al. Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS-mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: Subgroup results from the phase III IMpower150 trial. J. Immunother. Cancer 2022, 10, e003027. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Smits, R.; Hao, H.; He, C. Wnt/β-Catenin Signaling in Liver Cancers. Cancers 2019, 11, 926. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, A.X.; Abbas, A.R.; de Galarreta, M.R.; Guan, Y.; Lu, S.; Koeppen, H.; Zhang, W.; Hsu, C.-H.; He, A.R.; Ryoo, B.-Y.; et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 2022, 28, 1599–1611. [Google Scholar] [CrossRef] [PubMed]
- Forde, P.M.; Spicer, J.; Lu, S.; Provencio, M.; Mitsudomi, T.; Awad, M.M.; Felip, E.; Broderick, S.R.; Brahmer, J.R.; Swanson, S.J.; et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N. Engl. J. Med. 2022, 386, 1973–1985. [Google Scholar] [CrossRef] [PubMed]
- Provencio, M.; Nadal, E.; Insa, A.; García-Campelo, M.R.; Casal-Rubio, J.; Dómine, M.; Majem, M.; Rodríguez-Abreu, D.; Martínez-Martí, A.; De Castro Carpeño, J.; et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020, 21, 1413–1422. [Google Scholar] [CrossRef] [PubMed]
- Sheridan, C. Wnt is back in drugmakers’ sights, but is it druggable? Nat. Biotechnol. 2018, 36, 1028–1029. [Google Scholar] [CrossRef]
- Ganesh, S.; Shui, X.; Craig, K.P.; Park, J.; Wang, W.; Brown, B.D.; Abrams, M.T. RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade. Mol. Ther. 2018, 26, 2567–2579. [Google Scholar] [CrossRef]
- Ganesh, S.; Koser, M.L.; Cyr, W.A.; Chopda, G.R.; Tao, J.; Shui, X.; Ying, B.; Chen, D.; Pandya, P.; Chipumuro, E.; et al. Direct pharmacological inhibition of β-catenin by RNA interference in tumors of diverse origin. Mol. Cancer Ther. 2016, 15, 2143–2154. [Google Scholar] [CrossRef]
- Deldar Abad Paskeh, M.; Mirzaei, S.; Ashrafizadeh, M.; Zarrabi, A.; Sethi, G. Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways. J. Hepatocell. Carcinoma 2021, 8, 1415–1444. [Google Scholar] [CrossRef]
- Liu, Y.; Qi, X.; Donnelly, L.; Elghobashi-Meinhardt, N.; Long, T.; Zhou, R.W.; Sun, Y.; Wang, B.; Li, X. Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Nature 2022, 607, 816–822. [Google Scholar] [CrossRef]
- Janku, F.; de Vos, F.; de Miguel, M.; Forde, P.; Ribas, A.; Nagasaka, M.; Argiles, G.; Arance, A.M.; Calvo, A.; Giannakis, M.; et al. Abstract CT034: Phase I study of WNT974 + spartalizumab in patients (pts) with advanced solid tumors. Cancer Res. 2020, 80, CT034. [Google Scholar] [CrossRef]
- Kagey, M.H.; He, X. Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology. Br. J. Pharmacol. 2017, 174, 4637–4650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Haas, M.S.; Kagey, M.H.; Heath, H.; Schuerpf, F.; Rottman, J.B.; Newman, W. mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment. Mol. Cancer Res. 2021, 19, 717–725. [Google Scholar] [CrossRef] [PubMed]
- Klempner, S.J.; Bendell, J.C.; Villaflor, V.M.; Tenner, L.L.; Stein, S.M.; Rottman, J.B.; Naik, G.S.; Sirard, C.A.; Kagey, M.H.; Chaney, M.F.; et al. Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers. Mol. Cancer Ther. 2021, 20, 2240–2249. [Google Scholar] [CrossRef]
Gene | Genetic Aberration | Resulting Immune Editing | Reference |
---|---|---|---|
EGFR | Mutation | PD-L1↑, Tregs | [70,73] |
Myeloid cells↑ | [72] | ||
KRAS | Mutation | Myeloid cells↑, CD8 T cells↑, Tregs↑ | [72] |
MYC | Amplification | Macrophages↑, NK cells↓, T cells↓ | [78] |
Tregs↑, Lactic acid↑ | [79] | ||
STK11/LKB1 | Loss | Neutrophils↑, T cells↓, PD-L1↓ | [80,81] |
β-catenin target genes | Amplification | DC↓ | [82] |
Drug | Target | ICI Agent | Cancer Type | Trial Phase | Clinical Trial |
---|---|---|---|---|---|
LGK974 | PORCN | PDR001 | Solid tumors | I | NCT01351103 |
ETC-1922159 | PORCN | Pembrolizumab | Solid tumors | I | NCT02521844 |
CGX1321 | PORCN | Pembrolizumab | Solid/GI tumors | I | NCT02675946 |
RXC004 | PORCN | Nivolumab | Solid tumors | I | NCT03447470 |
RXC004 | PORCN | Nivolumab | Colorectal cancer | II | NCT04907539 |
DKN-01 | DKK1 | Pembrolizumab | Esophagogastric cancer | I | NCT02013154 |
DKN-01 | DKK1 | Nivolumab | Biliary tract cancer | II | NCT04057365 |
DKN-01 | DKK1 | Atezolizumab | Esophagogastric cancer | I/II | NCT04166721 |
DKN-01 | DKK1 | Tiselizumab | Esophagogastric cancer | II | NCT04363801 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Muto, S.; Enta, A.; Maruya, Y.; Inomata, S.; Yamaguchi, H.; Mine, H.; Takagi, H.; Ozaki, Y.; Watanabe, M.; Inoue, T.; et al. Wnt/β-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers. Biomedicines 2023, 11, 190. https://doi.org/10.3390/biomedicines11010190
Muto S, Enta A, Maruya Y, Inomata S, Yamaguchi H, Mine H, Takagi H, Ozaki Y, Watanabe M, Inoue T, et al. Wnt/β-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers. Biomedicines. 2023; 11(1):190. https://doi.org/10.3390/biomedicines11010190
Chicago/Turabian StyleMuto, Satoshi, Akio Enta, Yoshiyuki Maruya, Sho Inomata, Hikaru Yamaguchi, Hayato Mine, Hironori Takagi, Yuki Ozaki, Masayuki Watanabe, Takuya Inoue, and et al. 2023. "Wnt/β-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers" Biomedicines 11, no. 1: 190. https://doi.org/10.3390/biomedicines11010190