Immunotherapy Resistance in Solid Tumors: Mechanisms and Potential Solutions

Overview

Journal Cancer Biol Ther

Specialties Oncology
Pharmacology

Date 2024 Feb 23

PMID 38389121

Authors

Daniel S Lefler

Steven A Manobianco

Babar Bashir

Affiliations

Soon will be listed here.

Abstract

While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural immunity and immunotherapies through primary (innate) and secondary (acquired) mechanisms of resistance, and it considers available and emerging therapeutic approaches to overcoming immunotherapy resistance.

Citing Articles

A first evaluation of the efficacy of minibeam radiation therapy combined with an immune check point inhibitor in a model of glioma-bearing rats.

Iturri L, Jouglar E, Gilbert C, Espenon J, Juchaux M, Prezado Y Clin Transl Radiat Oncol. 2025; 51:100911.

PMID: 39898330 PMC: 11783053. DOI: 10.1016/j.ctro.2025.100911.

Spatial immune heterogeneity in a mouse tumor model after immunotherapy.

Smahel M, Johari S, Smahelova J, Pfeiferova L, Nunvar J Cancer Sci. 2024; 116(3):622-632.

PMID: 39624899 PMC: 11875765. DOI: 10.1111/cas.16421.

Adoptive T cell therapies for solid tumors: T(I)ME is of the essence.

Amwas N, Chiu C, Gumber D, Wang L EBioMedicine. 2024; 109:105449.

PMID: 39504721 PMC: 11570776. DOI: 10.1016/j.ebiom.2024.105449.

Hepatocellular Carcinoma Immunotherapy: Predictors of Response, Issues, and Challenges.

Rizzo A, Brunetti O, Brandi G Int J Mol Sci. 2024; 25(20).

PMID: 39456872 PMC: 11507510. DOI: 10.3390/ijms252011091.

Revealing the mechanism of natural product-induced immunogenic cell death: opening a new chapter in tumor immunotherapy.

Chen Y, Wang Z, Zhang C, Su Y, Zhou T, Hu K Front Immunol. 2024; 15:1470071.

PMID: 39445013 PMC: 11496055. DOI: 10.3389/fimmu.2024.1470071.

References

Glabman R, Choyke P, Sato N . Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy. Cancers (Basel). 2022; 14(16). PMC: 9405783. DOI: 10.3390/cancers14163906. View

Tawbi H, Schadendorf D, Lipson E, Ascierto P, Matamala L, Castillo Gutierrez E . Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022; 386(1):24-34. PMC: 9844513. DOI: 10.1056/NEJMoa2109970. View

Socinski M, Jotte R, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N . Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018; 378(24):2288-2301. DOI: 10.1056/NEJMoa1716948. View

Warburg O, Wind F, Negelein E . THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 2009; 8(6):519-30. PMC: 2140820. DOI: 10.1085/jgp.8.6.519. View

Dong Z, Zhong W, Zhang X, Su J, Xie Z, Liu S . Potential Predictive Value of and Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2017; 23(12):3012-3024. DOI: 10.1158/1078-0432.CCR-16-2554. View

Krenciute G, Prinzing B, Yi Z, Wu M, Liu H, Dotti G . Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants. Cancer Immunol Res. 2017; 5(7):571-581. PMC: 5746871. DOI: 10.1158/2326-6066.CIR-16-0376. View

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

Lowe M, Boothby I, Clancy S, Ahn R, Liao W, Nguyen D . Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. 2019; 4(24). PMC: 6975275. DOI: 10.1172/jci.insight.129756. View

Pallett L, Dimeloe S, Sinclair L, Byrne A, Schurich A . A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy. Immunother Adv. 2021; 1(1):ltab010. PMC: 8444990. DOI: 10.1093/immadv/ltab010. View

10.

Mitra M, Lancaster K, Adedeji A, Palanisamy G, Dave R, Zhong F . A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys. Toxicol Sci. 2020; 175(1):24-34. DOI: 10.1093/toxsci/kfaa024. View

11.

Ma N, Hua R, Yang Y, Liu Z, Pan J, Yu B . PES1 reduces CD8 T cell infiltration and immunotherapy sensitivity via interrupting ILF3-IL15 complex in esophageal squamous cell carcinoma. J Biomed Sci. 2023; 30(1):20. PMC: 10037800. DOI: 10.1186/s12929-023-00912-8. View

12.

Gadiyar V, Lahey K, Calianese D, Devoe C, Mehta D, Bono K . Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy. Cells. 2020; 9(10). PMC: 7599747. DOI: 10.3390/cells9102207. View

13.

Lindsay M, Schepers D, Bolar N, Doyle J, Gallo E, Fert-Bober J . Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012; 44(8):922-7. PMC: 3616632. DOI: 10.1038/ng.2349. View

14.

Suntharalingam G, Perry M, Ward S, Brett S, Castello-Cortes A, Brunner M . Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006; 355(10):1018-28. DOI: 10.1056/NEJMoa063842. View

15.

Baruch E, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L . Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2020; 371(6529):602-609. DOI: 10.1126/science.abb5920. View

16.

Qin R, Zhao C, Wang C, Xu W, Zhao J, Lin Y . Tryptophan potentiates CD8 T cells against cancer cells by TRIP12 tryptophanylation and surface PD-1 downregulation. J Immunother Cancer. 2021; 9(7). PMC: 8323461. DOI: 10.1136/jitc-2021-002840. View

17.

Taylor B, Balko J . Mechanisms of MHC-I Downregulation and Role in Immunotherapy Response. Front Immunol. 2022; 13:844866. PMC: 8920040. DOI: 10.3389/fimmu.2022.844866. View

18.

Vinay D, Ryan E, Pawelec G, Talib W, Stagg J, Elkord E . Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015; 35 Suppl:S185-S198. DOI: 10.1016/j.semcancer.2015.03.004. View

19.

Skoulidis F, Goldberg M, Greenawalt D, Hellmann M, Awad M, Gainor J . Mutations and PD-1 Inhibitor Resistance in -Mutant Lung Adenocarcinoma. Cancer Discov. 2018; 8(7):822-835. PMC: 6030433. DOI: 10.1158/2159-8290.CD-18-0099. View

20.

Narayan V, Barber-Rotenberg J, Jung I, Lacey S, Rech A, Davis M . PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022; 28(4):724-734. PMC: 10308799. DOI: 10.1038/s41591-022-01726-1. View