ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
Uncoupling CD4+ TIL-Mediated Tumor Killing from JAK-Signaling in Melanoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 18 citations in OpenAlex.
- Why CD4+ T cells matter in adoptive cell therapy for solid cancers.Immuno-oncology technology · 2026Review
- Hallmarks and correlates of effective adoptive cell immunotherapy for cancer.Nature reviews. Immunology · 2026Review
- Cytotoxic CD4Signal transduction and targeted therapy · 2026Review
- From Immunobiology to Clinical Application: Tumor-Infiltrating Lymphocytes in Melanoma.Journal of personalized medicine · 2026Review
- Cytotoxic CD4+ T cells in cancer: an emerging target for next-generation anticancer immunotherapy?Journal for immunotherapy of cancer · 2025Review
- β-adrenergic signaling blockade attenuates metastasis through activation of cytotoxic CD4 T cells.Nature communications · 2025Article
- Tumor Microenvironment in Melanoma-Characteristic and Clinical Implications.International journal of molecular sciences · 2025Review
- Emerging frontiers in adoptive cell therapies: innovations, challenges, and future perspectives.Medical oncology (Northwood, London, England) · 2025Review
- Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma.Cell reports. Medicine · 2025Article
- Peripheral immune biomarkers associated with response to adoptive cell therapy with tumor infiltrating lymphocytes.Clinical and experimental immunology · 2025Article
- TIL Therapy in Lung Cancer: Current Progress and Perspectives.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Review
- Deciphering CD4Molecular carcinogenesis · 2024Review
- Dose escalation study of a personalized peptide-based neoantigen vaccine (EVX-01) in patients with metastatic melanoma.Journal for immunotherapy of cancer · 2024Article
- CRISPR-Cas9 applications in T cells and adoptive T cell therapies.Cellular & molecular biology letters · 2024Review
- CD4+ TIL to the Rescue of Anti-PD-1 Failure by Targeting MHC-II.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- HLA-DR expression in melanoma: from misleading therapeutic target to potential immunotherapy biomarker.Frontiers in immunology · 2023Review
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10 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
purposeImpaired MHCI-presentation and insensitivity to immune effector molecules are common features of immune checkpoint blockade (ICB)-resistant tumors and can be, respectively, associated with loss of β2 microglobulin (B2M) or impaired IFNγ signaling. Patients with ICB-resistant tumors can respond to alternative immunotherapies, such as infusion of autologous tumor-infiltrating lymphocytes (TIL). CD4+ T cells can exert cytotoxic functions against tumor cells; however, it is unclear whether CD4+ T-cell responses can be exploited to improve the clinical outcomes of patients affected by ICB-resistant tumors. EXPERIMENTAL
designHere, we exploited CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing to reproduce immune-resistant tumor phenotypes via gene knockout (KO). To determine the role of cytotoxic CD4+ TILs in ICB-resistant tumors, we investigated CD4+ TIL-mediated cytotoxicity in matched pairs of TILs and autologous melanoma cell lines, used as a model of patient-specific immune-tumor interaction. Around 40% of melanomas constitutively express MHC Class II molecules; hence, melanomas with or without natural constitutive MHC Class II expression (MHCIIconst+ or MHCIIconst-) were used.
resultsCD4+ TIL-mediated cytotoxicity was not affected by B2M loss but was dependent on the expression of CIITA. MHCIIconst+ melanomas were killed by tumor-specific CD4+ TILs even in the absence of IFNγ-mediated MHCII upregulation, whereas IFNγ was necessary for CD4+ TIL-mediated cytotoxicity against MHCIIconst- melanomas. Notably, although tumor-specific CD4+ TILs did not kill JAK1KO MHCIIconst- melanomas even after IFNγ stimulation, sensitivity to CD4+ TIL-mediated cytotoxicity was maintained by JAK1KO MHCIIconst+ melanomas.
conclusionsIn conclusion, our data indicate that exploiting tumor-specific cytotoxic CD4+ TILs could help overcome resistance to ICB mediated by IFNγ-signaling loss in MHCIIconst+ melanomas. See related commentary by Betof Warner and Luke, p. 3829.
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