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MUC1 as a target for CAR-T therapy in head and neck squamous cell carinoma. ​

Literature Information ​

DOI10.1002/cam4.2733
PMID31800160
JournalCancer medicine
Impact Factor3.1
JCR QuartileQ2
Publication Year2020
Times Cited61
KeywordsCAR-T, IL22, MUC1, head and neck squamous cell carcinoma
Literature TypeJournal Article, Research Support, Non-U.S. Gov't
ISSN2045-7634
Pages640-652
Issue9(2)
AuthorsZi Mei, Kai Zhang, Alfred King-Yin Lam, Junwen Huang, Feng Qiu, Bin Qiao, Yi Zhang

TL;DR ​

This study explores the potential of chimeric antigen receptor (CAR) T cell therapy targeting MUC1 for treating head and neck squamous cell carcinoma (HNSCC), addressing challenges such as tumor structure and immunosuppression. The researchers demonstrated that a fourth-generation CAR, which secretes IL22, significantly enhances T cell cytotoxicity against MUC1+ HNSCC cells, suggesting a promising therapeutic strategy for patients.

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CAR-T · IL22 · MUC1 · head and neck squamous cell carcinoma

Abstract ​

The modification of chimeric antigen receptor (CAR) endowing T cells with tumor-specific cytotoxicity induces antitumor immunity. However, the structural characteristics of solid tumors, the loss of specific antigens, and the strong immunosuppressive environment are challenges to treat solid tumors with CAR-T therapy. The purpose of our study was to find and verify the potentials of CAR-T therapies for patients with head and neck squamous cell carcinoma (HNSCC). First, we selected MUC1 as our research target and verified its differential expression in cancer tissues and adjacent non-neoplastic tissues (ANNT). Next, we constructed a second-generation CAR and validated the cytotoxic function in vitro. In our study, we found that exogenous addition human IL22 recombinant protein could increase the MUC1 expression and enhance the function of T cells. In addition, we constructed a fourth-generation CAR that secretes IL22. Finally, we verified the antitumor function of two different CAR-T cells in vitro and in vivo, respectively. CAR-MUC1-IL22 T cells were found to have a stronger and more effective cytotoxic function against MUC1 + HNSCC cells. Taken together, these results demonstrate the potential effectiveness of CAR-T in the treatment of patients with HNSCC and provide evidence-based of MUC1 + CAR-T therapy.

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Primary Questions Addressed ​

  1. What are the potential challenges and limitations of targeting MUC1 in CAR-T therapy for HNSCC?
  2. How does the expression of MUC1 in HNSCC compare to other types of head and neck cancers?
  3. What role does the tumor microenvironment play in the efficacy of CAR-T therapies targeting MUC1?
  4. Are there alternative antigens to MUC1 that could be explored for CAR-T therapy in HNSCC?
  5. How might the incorporation of IL22 in CAR-T design affect the overall treatment strategy for HNSCC patients?

Key Findings ​

Research Background and Purpose ​

Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer type with poor prognosis despite existing treatments such as surgery, chemotherapy, and radiation. The study aimed to explore the potential of chimeric antigen receptor T (CAR-T) cell therapy targeting MUC1, a mucin protein overexpressed in HNSCC, to improve therapeutic outcomes for patients.

Main Methods/Materials/Experimental Design ​

The research employed a systematic approach involving the following key steps:

  1. Selection of Target: MUC1 was chosen based on its differential expression in HNSCC tissues compared to adjacent non-neoplastic tissues.
  2. CAR Construction: Two types of CAR constructs were developed:
    • Second-Generation CAR: Comprising MUC1-specific single-chain variable fragment (scFv), 4-1BB, and CD3ζ signaling domains.
    • Fourth-Generation CAR: Engineered to secrete IL22 in addition to targeting MUC1.
  3. Cell Culture: HNSCC cell lines (HN4, Cal27, Cal33, SCC15, SCC25) were cultured alongside immortalized oral epithelial cells.
  4. T Cell Preparation: CD3+ T cells were isolated from human peripheral blood and activated for transduction with CAR constructs.
  5. In Vitro Assays: Cytotoxicity assays were conducted to evaluate the effectiveness of CAR-T cells against HNSCC cell lines, measuring cytokine production and apoptosis rates.
  6. In Vivo Studies: NOD/SCID mouse models were utilized to assess tumor growth inhibition following CAR-T cell infusion.
Mermaid diagram

Key Results and Findings ​

  • MUC1 Expression: MUC1 was significantly overexpressed in HNSCC tissues compared to adjacent non-neoplastic tissues.
  • Cytotoxicity: CAR-MUC1 T cells demonstrated superior cytotoxic effects against MUC1+ HNSCC cell lines compared to control T cells. The fourth-generation CAR-MUC1-IL22 T cells exhibited enhanced killing ability and proliferation.
  • IL22 Role: Exogenous IL22 increased MUC1 expression and improved T cell differentiation, leading to enhanced cytotoxicity at lower effector-to-target (E/T) ratios.
  • In Vivo Efficacy: Mice treated with CAR-MUC1-IL22 T cells showed significantly reduced tumor growth compared to control groups.

Main Conclusions/Significance/Innovation ​

The study presents a promising strategy for HNSCC treatment through MUC1-targeted CAR-T therapy, particularly with the incorporation of IL22, which enhances T cell function and tumor targeting. The findings indicate that CAR-MUC1-IL22 T cells could offer a novel therapeutic approach for patients with HNSCC, potentially improving treatment outcomes and survival rates.

Research Limitations and Future Directions ​

  • Limitations: The study primarily focused on preclinical models, which may not fully replicate human immune responses. The potential for off-target effects and long-term efficacy in human subjects remains to be evaluated.
  • Future Directions: Further research should explore the safety and effectiveness of CAR-MUC1-IL22 therapy in clinical trials, investigate the mechanisms of IL22's effects on T cell dynamics, and develop patient-derived xenograft models to better simulate human tumor microenvironments.

References ​

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Literatures Citing This Work ​

  1. MUC1 as a target for CAR-T therapy in head and neck squamous cell carinoma. - Zi Mei;Kai Zhang;Alfred King-Yin Lam;Junwen Huang;Feng Qiu;Bin Qiao;Yi Zhang - Cancer medicine (2020)
  2. Antibodies specific for disease-associated antigens (DAA) expressed in non-malignant diseases reveal potential new tumor-associated antigens (TAA) for immunotherapy or immunoprevention. - Camille Jacqueline;Olivera J Finn - Seminars in immunology (2020)
  3. Gene modification strategies for next-generation CAR T cells against solid cancers. - Yonggui Tian;Yilu Li;Yupei Shao;Yi Zhang - Journal of hematology & oncology (2020)
  4. Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck. - Qiang Xu;Meiyu Fang;Jing Zhu;Haoru Dong;Jun Cao;Lin Yan;Fransisca Leonard;Felix Oppel;Holger Sudhoff;Andreas M Kaufmann;Andreas E Albers;Xu Qian - International journal of biological sciences (2020)
  5. Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials. - Philippe Rochigneux;Brice Chanez;Bernadette De Rauglaudre;Emmanuel Mitry;Christian Chabannon;Marine Gilabert - Cancers (2021)
  6. Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma. - Kamonlapat Supimon;Thanich Sangsuwannukul;Jatuporn Sujjitjoon;Nattaporn Phanthaphol;Thaweesak Chieochansin;Naravat Poungvarin;Sopit Wongkham;Mutita Junking;Pa-Thai Yenchitsomanus - Scientific reports (2021)
  7. Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma. - Florencia Veigas;Yamil D Mahmoud;Joaquin Merlo;Adriana Rinflerch;Gabriel Adrian Rabinovich;María Romina Girotti - Cancers (2021)
  8. Immune deserts in head and neck squamous cell carcinoma: A review of challenges and opportunities for modulating the tumor immune microenvironment. - Janice L Farlow;J Chad Brenner;Yu L Lei;Steven B Chinn - Oral oncology (2021)
  9. A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine. - Mahdi Abdoli Shadbad;Nima Hemmat;Vahid Khaze Shahgoli;Afshin Derakhshani;Farzad Baradaran;Oronzo Brunetti;Rossella Fasano;Renato Bernardini;Nicola Silvestris;Behzad Baradaran - Frontiers in immunology (2021)
  10. Novel Cellular Therapies for Hepatocellular Carcinoma. - Harriet Roddy;Tim Meyer;Claire Roddie - Cancers (2022)

... (51 more literatures)

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