PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors

Duhen, Rebekka; Fesneau, Olivier; Samson, Kimberly; Frye, Alexandra K.; Beymer, Michael; Ross, David; Tran, Eric; Bernard, Brady; Weinberg, Andrew D.; Duhen, Thomas

doi:10.1172/jci156821

Cited by 45 publications

(40 citation statements)

References 31 publications

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“…Physical interaction of PD-1 + ICOS + Th1 or Th17 cells with MHC II + DCs in the TME would likely enhance cross-priming of antitumor CD8 + T cells within the tumor-associated TLSs, allowing for local antitumor T cell repertoire expansion and diversification that is distinguishable from T cell priming in the periphery. It is intriguing that Duhen et al ( 11 ) report that the presence of stromally located DP CD4 + Th cells was strongly associated with CD39 + CD103 + CD8 + TIL (known to be enriched for tumor reactivity) content in the TME of HNSCC samples, but did not find such an association in CRC specimens. Differences in TME content of regulatory immune cells (i.e., Foxp3 + CD4 + Tregs and myeloid-derived suppressor cells) or tumor-intrinsic immune suppression mechanisms were not accounted for in these analyses and could therefore serve as potential mechanisms underlying the divergence in the immune cell interactions operating in the TME of HNSCC compared with that of CRC.…”

Section: A Broader Systems Biology For Tumor Th Cells?mentioning

confidence: 98%

“…In this issue of the JCI , Duhen et al ( 11 ) profiled the tumor immune microenvironment in patients with HPV + head and neck squamous cell carcinoma (HNSCC) or microsatellite-stable colorectal carcinoma (CRC) and identified a subset of CD4 + Th cells coexpressing the immune checkpoint and costimulatory molecules programmed cell death 1 (PD-1) and ICOS. These double-positive (DP) cells were devoid of immune-suppressive activity and enriched in functional attributes associated with inflammatory T cell and humoral responses.…”

Section: Finding Cognate Th Cells In the Tmementioning

confidence: 99%

“…Based on tumor imaging data provided by Duhen et al, PD-1 + ICOS + CD4 + TILs and MHC II + antigen-presenting cells (APCs) were identified in close proximity within the tumor stroma ( 11 ). Such intercellular interactions may potentiate and sustain PD-1 + ICOS + CD4 + TILs.…”

Section: A Broader Systems Biology For Tumor Th Cells?mentioning

confidence: 99%

“…Such intercellular interactions may potentiate and sustain PD-1 + ICOS + CD4 + TILs. Although Duhen and colleagues did not pedigree the Th-associated MHC II + APCs by characterizing surface markers, including ICOS ligand (ICOSL) ( 11 ), B cells and macrophages express the highest levels of ICOSL within the TME ( 12 ). Since ICOS-ICOSL interactions support tissue-resident memory development ( 13 ) and T follicular helper (Tfh) survival and function ( 14 ), B cells and macrophages may constitute the principal Th-associated APCs in tumors.…”

Section: A Broader Systems Biology For Tumor Th Cells?mentioning

confidence: 99%

“…So how is this information instructive for improving response rates to interventional immunotherapies in the setting of HNSCC and CRC or other forms of solid cancer? As Duhen and authors note, their findings suggest the possibility of sorting functional DP CD4 + TILs from tumor biopsy material to provide an enriched source of nonexhausted, Treg-depleted, tumor antigen–specific T cells that could be expanded ex vivo for subsequent transfer back into the patient as an adoptive immunotherapy ( 11 , 16 , 17 ). Alternatively, TCRs cloned from DP CD4 + TILs reactive against patient-matched tumor (neo)antigens could be used to develop TCR-engineered T cells from the patient’s peripheral blood for adoptive transfer as an interventional therapy ( 16 , 17 ).…”

Section: Translational Ramifications Of These Findingsmentioning

confidence: 99%

See 4 more Smart Citations

Finding the right help in the tumor microenvironment

Filderman¹,

Storkus²

2022

Journal of Clinical Investigation

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Tumor-infiltrating lymphocytes (TILs) contain substantial numbers of CD4 + T cells mediating pro- and antitumor functions. While CD4 + Tregs are well characterized and known to promote tumor immune evasion, the fingerprint of CD4 + Th cells that recognizes tumor antigens and serves to restrict disease progression has remained poorly discriminated. In this issue of the JCI , Duhen et al. analyzed tumors from patients with head and neck squamous cell carcinoma or colon carcinoma and identified a unique programmed cell death 1–positive, ICOS1-positive (PD-1 + ICOS1 + ) subpopulation of CD4 + TILs highly enriched for the ability to recognize tumor-associated antigens. These cells localized proximally to MHC II + antigen-presenting cells and CD8 + T cells within tumors, where they appeared to proliferate and function almost exclusively as Th cells. These potentially therapeutic Th cells can be monitored for patient prognosis and are expected to have substantial utility in developing personalized adoptive cell– and vaccine-based immunotherapeutic approaches for improving patient outcomes.

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Section: A Broader Systems Biology For Tumor Th Cells?mentioning

confidence: 98%

Section: Finding Cognate Th Cells In the Tmementioning

confidence: 99%

Section: A Broader Systems Biology For Tumor Th Cells?mentioning

confidence: 99%

Section: A Broader Systems Biology For Tumor Th Cells?mentioning

confidence: 99%

Section: Translational Ramifications Of These Findingsmentioning

confidence: 99%

See 3 more Smart Citations

Finding the right help in the tumor microenvironment

Filderman¹,

Storkus²

2022

Journal of Clinical Investigation

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ELOVL6 promotes the progression of head and neck squamous cell carcinoma via activating WNT/β‐catenin pathway

Wang,

Liu,

et al. 2024

Molecular Carcinogenesis

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This study was to explore the role of ELOVL6 in the development of head and neck squamous cell carcinoma (HNSCC). Considering its previously identified oncogenic role in hepatocellular carcinoma. ELOVL6 gene expression, clinicopathological analysis, enrichment analysis, and immune infiltration analysis were based on the data from Gene Expression Omnibus and The Cancer Genome Atlas, with additional bioinformatics analyses performed. Human HNSCC tissue microarray and cell lines were used. The expression of ELOVL6 in HNSCC was detected by quantitative polymerase chain reaction, immunohistochemistry assay, and western blot analysis. The proliferation ability of HNSCC cells, invasion, and apoptosis were evaluated using cell counting kit‐8 method, Transwell assay, and flow cytometry, respectively. Based on the data derived from the cancer databases and our HNSCC cell and tissue studies, we found that ELOVL6 was overexpressed in HNSCC. Moreover, ELOVL6 expression level had a positive correlation with clinicopathology of HNSCC. Gene set enrichment analysis showed that ELOVL6 affected the occurrence of HNSCC through WNT signaling pathway. Functional experiments demonstrated that ELOVL6 knockdown inhibited the proliferation and invasion of HNSCC cells while promoting apoptosis. Additionally, compound 3f, an agonist of WNT/β‐catenin signaling pathway, enhances the effect of ELOVL6 on the progression of HNSCC cells. ELOVL6 is upregulated in HNSCC and promotes the development of HNSCC cells by inducing WNT/β‐catenin signaling pathway. ELOVL6 stands a potential target for the treatment of HNSCC and a prognosis indicator of human HNSCC.

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Successful ex vivo expansion of tumor infiltrating lymphocytes with systemic chemotherapy prior to surgical resection

Balzeau,

Ravindran,

Wang

et al. 2023

Cancer Immunol Immunother

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Tumor In ltrating Lymphocytes (TIL) have demonstrated e cacious clinical outcomes for many patients with various types of solid cancers, including melanoma, gastrointestinal cancer, lung cancer, and head & neck cancer. Currently, majority of clinical trials require that patients did not receive systemic therapy right before tumor tissue resection to avoid the interference of chemotherapy in the ex vivo TIL expansion. The primary disadvantage of this strategy is limiting the accessibility of TIL therapy for many eligible cancer patients. Over the past decade, substantial progress has been made for ex vivo expansion technologies in T cells. In this study, we investigated the possibility of enrolling patients who underwent chemotherapy prior to surgical resection. We collected seventeen tumor tissues from treatment naive cases, and ve from cases that underwent chemotherapies. Cancer indications enrolled in this study were colorectal, lung, and brain cancers from both primary and metastasis cancers. TILs from these tumors were expanded ex vivo to 2.1E8 on average, with an overall success rate of 90.9%. Subsequently, TIL phenotypes and cytokine production were analyzed using ow cytometry and ELISA, respectively. We demonstrated functional TIL expansion from tumor tissues despite chemotherapy prior to surgical resection. We observed no signi cant phenotypic or functional differences nor changes between groups with and without chemotherapy. TIL expansion rate and characteristics were similar regardless of chemotherapy prior to resection, thereby providing a possibility to recruit patients with the most recent chemotherapy history in TIL therapy trials.

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PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors

Cited by 45 publications

References 31 publications

Finding the right help in the tumor microenvironment

Finding the right help in the tumor microenvironment

ELOVL6 promotes the progression of head and neck squamous cell carcinoma via activating WNT/β‐catenin pathway

Successful ex vivo expansion of tumor infiltrating lymphocytes with systemic chemotherapy prior to surgical resection

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