Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Co-mutation of TP53 and TTN is Correlated with the Efficacy of Immunotherapy in Lung Squamous Cell Carcinoma

Author(s): Kaijun Ying, Li Zou, Daquan Wang, Rao Wang and Jun Qian*

Volume 27, Issue 18, 2024

Published on: 23 October, 2023

Page: [2699 - 2711] Pages: 13

DOI: 10.2174/0113862073246841230922052004

Price: $65

Abstract

Background: Immunotherapy has been a promising treatment in advanced lung cancer. However, only a few patients could benefit from it. Herein, we aimed to explore mutationrelated predictive biomarkers in lung squamous cell carcinoma (LUSC), which could help develop clinical immunotherapy strategies and screen beneficial populations.

Methods: Co-occurrence and mutually exclusive analysis was conducted on the TCGA-LUSC cohort. Correlations between the gene mutation status and tumor mutation burden (TMB) levels, and neo-antigen levels were analyzed by Wilcoxon test. Kaplan-Meier method was employed to analyze the progression-free survival (PFS) of lung cancer patients with immunotherapy. Gene set enrichment analysis (GSEA) was used to investigate the functional changes affected by TP53mut/TTNmut. The immune cell infiltration landscape in co-mutation subgroups was analyzed using CIBERSORT.

Results: 1) TP53, TTN, CSMD3, MUC16, RYR2, LRP1B, USH2A, SYNE1, ZFHX4, FAM135B, KMT2D, and NAV3 were frequently mutated in LUSC patients. 2) TMB levels in highly mutated groups were higher than that in wild type groups. 3) There were higher neoantigen levels in mutation group compared to the wild-type group, and LUSC patients in mutation group had longer PFS. 4) TP53mut/TTNmut co-mutation group exhibited higher TMB levels and better response to immunotherapy. 5) A host of immune-related signaling pathways was inhibited in TP53mut/TTNmut subgroup. 6) There were more T follicular helper cells and NK cells were in TP53mut/TTNmut subgroup than in the WT subgroup.

Conclusion: The LUSC patients with TP53 and TTN co-mutation had higher TMB levels and better response to immunotherapy. The TP53 and TTN co-mutation is a promising novel biomarker to assist LUSC immunotherapy evaluation.

« Previous Next »
[1]
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(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Nicholson, A.G.; Tsao, M.S.; Beasley, M.B.; Borczuk, A.C.; Brambilla, E.; Cooper, W.A.; Dacic, S.; Jain, D.; Kerr, K.M.; Lantuejoul, S.; Noguchi, M.; Papotti, M.; Rekhtman, N.; Scagliotti, G.; van Schil, P.; Sholl, L.; Yatabe, Y.; Yoshida, A.; Travis, W.D. The 2021 WHO classification of lung tumors: Impact of advances since 2015. J. Thorac. Oncol., 2022, 17(3), 362-387.
[http://dx.doi.org/10.1016/j.jtho.2021.11.003] [PMID: 34808341]
[3]
Chambers, C.A.; Kuhns, M.S.; Egen, J.G.; Allison, J.P. CTLA-4-mediated inhibition in regulation of T cell responses: Mechanisms and manipulation in tumor immunotherapy. Annu. Rev. Immunol., 2001, 19(1), 565-594.
[http://dx.doi.org/10.1146/annurev.immunol.19.1.565] [PMID: 11244047]
[4]
Baumeister, S.H.; Freeman, G.J.; Dranoff, G.; Sharpe, A.H. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol., 2016, 34(1), 539-573.
[http://dx.doi.org/10.1146/annurev-immunol-032414-112049] [PMID: 26927206]
[5]
Zarour, H.M. Reversing T-cell dysfunction and exhaustion in cancer. Clin. Cancer Res., 2016, 22(8), 1856-1864.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1849] [PMID: 27084739]
[6]
Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; Carcereny, E.; Ahn, M.J.; Felip, E.; Lee, J.S.; Hellmann, M.D.; Hamid, O.; Goldman, J.W.; Soria, J.C.; Dolled-Filhart, M.; Rutledge, R.Z.; Zhang, J.; Lunceford, J.K.; Rangwala, R.; Lubiniecki, G.M.; Roach, C.; Emancipator, K.; Gandhi, L. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med., 2015, 372(21), 2018-2028.
[http://dx.doi.org/10.1056/NEJMoa1501824] [PMID: 25891174]
[7]
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.; Barlesi, F.; Kohlhäufl, M.; Arrieta, O.; Burgio, M.A.; Fayette, J.; Lena, H.; Poddubskaya, E.; Gerber, D.E.; Gettinger, S.N.; Rudin, C.M.; Rizvi, N.; Crinò, L.; Blumenschein, G.R., Jr; Antonia, S.J.; Dorange, C.; Harbison, C.T.; Graf Finckenstein, F.; Brahmer, J.R. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med., 2015, 373(17), 1627-1639.
[http://dx.doi.org/10.1056/NEJMoa1507643] [PMID: 26412456]
[8]
Vokes, E.E.; Ready, N.; Felip, E.; Horn, L.; Burgio, M.A.; Antonia, S.J.; Arén Frontera, O.; Gettinger, S.; Holgado, E.; Spigel, D.; Waterhouse, D.; Domine, M.; Garassino, M.; Chow, L.Q.M.; Blumenschein, G., Jr; Barlesi, F.; Coudert, B.; Gainor, J.; Arrieta, O.; Brahmer, J.; Butts, C.; Steins, M.; Geese, W.J.; Li, A.; Healey, D.; Crinò, L. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann. Oncol., 2018, 29(4), 959-965.
[http://dx.doi.org/10.1093/annonc/mdy041] [PMID: 29408986]
[9]
Rittmeyer, A.; Barlesi, F.; Waterkamp, D.; Park, K.; Ciardiello, F.; von Pawel, J.; Gadgeel, S.M.; Hida, T.; Kowalski, D.M.; Dols, M.C.; Cortinovis, D.L.; Leach, J.; Polikoff, J.; Barrios, C.; Kabbinavar, F.; Frontera, O.A.; De Marinis, F.; Turna, H.; Lee, J.S.; Ballinger, M.; Kowanetz, M.; He, P.; Chen, D.S.; Sandler, A.; Gandara, D.R. 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(10066), 255-265.
[http://dx.doi.org/10.1016/S0140-6736(16)32517-X] [PMID: 27979383]
[10]
Garassino, M.C.; Cho, B.C.; Kim, J.H.; Mazières, J.; Vansteenkiste, J.; Lena, H.; Corral Jaime, J.; Gray, J.E.; Powderly, J.; Chouaid, C.; Bidoli, P.; Wheatley-Price, P.; Park, K.; Soo, R.A.; Huang, Y.; Wadsworth, C.; Dennis, P.A.; Rizvi, N.A.; Paz-Ares Rodriguez, L.; Novello, S.; Hiret, S.; Schmid, P.; Laack, E.; Califano, R.; Maemondo, M.; Kim, S-W.; Chaft, J.; Vicente Baz, D.; Berghmans, T.; Kim, D-W.; Surmont, V.; Reck, M.; Han, J-Y.; Holgado Martin, E.; Belda Iniesta, C.; Oe, Y.; Chella, A.; Chopra, A.; Robinet, G.; Soto Parra, H.; Thomas, M.; Cheema, P.; Katakami, N.; Su, W-C.; Kim, Y-C.; Wolf, J.; Lee, J-S.; Saka, H.; Milella, M.; Ramos Garcia, I.; Sibille, A.; Yokoi, T.; Kang, E.J.; Atagi, S.; Spaeth-Schwalbe, E.; Nishio, M.; Imamura, F.; Gabrail, N.; Veillon, R.; Derijcke, S.; Maeda, T.; Zylla, D.; Kubiak, K.; Santoro, A.; Uy, M.N.; Lucien Geater, S.; Italiano, A.; Kowalski, D.; Barlesi, F.; Chen, Y-M.; Spigel, D.; Chewaskulyong, B.; Garcia Gomez, R.; Alvarez Alvarez, R.; Yang, C-H.; Hsia, T-C.; Denis, F.; Sakai, H.; Vincent, M.; Goto, K.; Bosch-Barrera, J.; Weiss, G.; Canon, J-L.; Scholz, C.; Aglietta, M.; Kemmotsu, H.; Azuma, K.; Bradbury, P.; Feld, R.; Chachoua, A.; Jassem, J.; Juergens, R.; Palmero Sanchez, R.; Malcolm, A.; Vrindavanam, N.; Kubota, K.; Waller, C.; Waterhouse, D.; Coudert, B.; Mark, Z.; Satouchi, M.; Chang, G-C.; Herzmann, C.; Chaudhry, A.; Giridharan, S.; Hesketh, P.; Ikeda, N.; Boccia, R.; Iannotti, N.; Haigentz, M.; Reynolds, J.; Querol, J.; Nakagawa, K.; Sugawara, S.; Tan, E.H.; Hirashima, T.; Gettinger, S.; Kato, T.; Takeda, K.; Juan Vidal, O.; Mohn-Staudner, A.; Panwalkar, A.; Daniel, D.; Kobayashi, K.; Ladrera, G.E.I.; Schulte, C.; Sebastian, M.; Cernovska, M.; Coupkova, H.; Havel, L.; Pauk, N.; Singh, J.; Murakami, S.; Csoszi, T.; Losonczy, G.; Price, A.; Anderson, I.; Iqbal, M.; Torri, V.; Juhasz, E.; Khanani, S.; Koubkova, L.; Levy, B.; Page, R.; Bocskei, C.; Crinò, L.; Einspahr, D.; Hagenstad, C.; Juat, N.; Overton, L.; Garrison, M.; Szalai, Z. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol., 2018, 19(4), 521-536.
[http://dx.doi.org/10.1016/S1470-2045(18)30144-X] [PMID: 29545095]
[11]
Hellmann, M.D.; Rizvi, N.A.; Goldman, J.W.; Gettinger, S.N.; Borghaei, H.; Brahmer, J.R.; Ready, N.E.; Gerber, D.E.; Chow, L.Q.; Juergens, R.A.; Shepherd, F.A.; Laurie, S.A.; Geese, W.J.; Agrawal, S.; Young, T.C.; Li, X.; Antonia, S.J. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): Results of an open-label, phase 1, multicohort study. Lancet Oncol., 2017, 18(1), 31-41.
[http://dx.doi.org/10.1016/S1470-2045(16)30624-6] [PMID: 27932067]
[12]
High TMB Predicts Immunotherapy Benefit. Cancer Discov., 2018, 8(6), 668.
[http://dx.doi.org/10.1158/2159-8290.CD-NB2018-048] [PMID: 29661758]
[13]
Dudley, J.C.; Lin, M.T.; Le, D.T.; Eshleman, J.R. Microsatellite instability as a biomarker for PD-1 blockade. Clin. Cancer Res., 2016, 22(4), 813-820.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1678] [PMID: 26880610]
[14]
Olivares-Hernández, A.; del Barco Morillo, E.; Parra Pérez, C.; Miramontes-González, J.P.; Figuero-Pérez, L.; Martín-Gómez, T.; Escala-Cornejo, R.; Bellido Hernández, L.; González Sarmiento, R.; Cruz-Hernández, J.J.; Ludeña de la Cruz, M.D. Influence of dna mismatch repair (MMR) system in survival and response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC): Retrospective analysis. Biomedicines, 2022, 10(2), 360.
[http://dx.doi.org/10.3390/biomedicines10020360] [PMID: 35203569]
[15]
Yi, M.; Qin, S.; Zhao, W.; Yu, S.; Chu, Q.; Wu, K. The role of neoantigen in immune checkpoint blockade therapy. Exp. Hematol. Oncol., 2018, 7(1), 28.
[http://dx.doi.org/10.1186/s40164-018-0120-y] [PMID: 30473928]
[16]
Hellmann, M.D.; Nathanson, T.; Rizvi, H.; Creelan, B.C.; Sanchez-Vega, F.; Ahuja, A.; Ni, A.; Novik, J.B.; Mangarin, L.M.B.; Abu-Akeel, M.; Liu, C.; Sauter, J.L.; Rekhtman, N.; Chang, E.; Callahan, M.K.; Chaft, J.E.; Voss, M.H.; Tenet, M.; Li, X.M.; Covello, K.; Renninger, A.; Vitazka, P.; Geese, W.J.; Borghaei, H.; Rudin, C.M.; Antonia, S.J.; Swanton, C.; Hammerbacher, J.; Merghoub, T.; McGranahan, N.; Snyder, A.; Wolchok, J.D. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell, 2018, 33(5), 843-852.e4.
[http://dx.doi.org/10.1016/j.ccell.2018.03.018] [PMID: 29657128]
[17]
Rizvi, H.; Sanchez-Vega, F.; La, K.; Chatila, W.; Jonsson, P.; Halpenny, D.; Plodkowski, A.; Long, N.; Sauter, J.L.; Rekhtman, N.; Hollmann, T.; Schalper, K.A.; Gainor, J.F.; Shen, R.; Ni, A.; Arbour, K.C.; Merghoub, T.; Wolchok, J.; Snyder, A.; Chaft, J.E.; Kris, M.G.; Rudin, C.M.; Socci, N.D.; Berger, M.F.; Taylor, B.S.; Zehir, A.; Solit, D.B.; Arcila, M.E.; Ladanyi, M.; Riely, G.J.; Schultz, N.; Hellmann, M.D. Molecular determinants of response to anti–programmed cell death (PD)-1 and Anti–programmed death-ligand 1 (PD-L1) blockade in patients with non–small-cell lung cancer profiled with targeted next-generation sequencing. J. Clin. Oncol., 2018, 36(7), 633-641.
[http://dx.doi.org/10.1200/JCO.2017.75.3384] [PMID: 29337640]
[18]
Rizvi, N.A.; Hellmann, M.D.; Snyder, A.; Kvistborg, P.; Makarov, V.; Havel, J.J.; Lee, W.; Yuan, J.; Wong, P.; Ho, T.S.; Miller, M.L.; Rekhtman, N.; Moreira, A.L.; Ibrahim, F.; Bruggeman, C.; Gasmi, B.; Zappasodi, R.; Maeda, Y.; Sander, C.; Garon, E.B.; Merghoub, T.; Wolchok, J.D.; Schumacher, T.N.; Chan, T.A. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science, 2015, 348(6230), 124-128.
[http://dx.doi.org/10.1126/science.aaa1348] [PMID: 25765070]
[19]
Newman, A.M.; Liu, C.L.; Green, M.R.; Gentles, A.J.; Feng, W.; Xu, Y.; Hoang, C.D.; Diehn, M.; Alizadeh, A.A. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods, 2015, 12(5), 453-457.
[http://dx.doi.org/10.1038/nmeth.3337] [PMID: 25822800]
[20]
Xu, F.; Lin, H.; He, P.; He, L.; Chen, J.; Lin, L.; Chen, Y. A TP53 -associated gene signature for prediction of prognosis and therapeutic responses in lung squamous cell carcinoma. OncoImmunology, 2020, 9(1), 1731943.
[http://dx.doi.org/10.1080/2162402X.2020.1731943] [PMID: 32158625]
[21]
Xie, X.; Tang, Y.; Sheng, J.; Shu, P.; Zhu, X.; Cai, X.; Zhao, C.; Wang, L.; Huang, X. Titin mutation is associated with tumor mutation burden and promotes antitumor immunity in lung squamous cell carcinoma. Front. Cell Dev. Biol., 2021, 9, 761758.
[http://dx.doi.org/10.3389/fcell.2021.761758] [PMID: 34746153]
[22]
Xue, D.; Lin, H.; Lin, L.; Wei, Q.; Yang, S.; Chen, X. TTN/TP53 mutation might act as the predictor for chemotherapy response in lung adenocarcinoma and lung squamous carcinoma patients. Transl. Cancer Res., 2021, 10(3), 1284-1294.
[http://dx.doi.org/10.21037/tcr-20-2568] [PMID: 35116455]
[23]
Lu, J.; Zhong, R.; Lou, Y.; Hu, M.; Yang, Z.; Wang, Y.; Chen, Y.; Zou, B.; Zhang, W.; Wang, H.; Han, B. TP53 mutation status and biopsy lesion type determine the immunotherapeutic stratification in non-small-cell lung cancer. Front. Immunol., 2021, 12, 732125.
[http://dx.doi.org/10.3389/fimmu.2021.732125] [PMID: 34603310]
[24]
Skoulidis, F.; Heymach, J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat. Rev. Cancer, 2019, 19(9), 495-509.
[http://dx.doi.org/10.1038/s41568-019-0179-8] [PMID: 31406302]
[25]
Zhang, C.; Wang, K.; Lin, J.; Wang, H. Non-small-cell lung cancer patients harboring TP53/KRAS co-mutation could benefit from a PD-L1 inhibitor. Future Oncol., 2022, 18(27), 3031-3041.
[http://dx.doi.org/10.2217/fon-2022-0295] [PMID: 36065989]
[26]
Yu, J.; Fan, Z.; Zhou, Z.; Zhang, P.; Bai, J.; Li, X.; Tang, M.; Fan, N.; Wu, X.; Nie, X.; Chen, X.; Ma, D.; Chen, X.; Cui, L.; Xia, X.; Yang, L.; Yi, X.; Li, L. TP53 and LRP1B co-wild predicts improved survival for patients with LUSC receiving Anti-PD-L1 immunotherapy. Cancers, 2022, 14(14), 3382.
[http://dx.doi.org/10.3390/cancers14143382] [PMID: 35884443]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy