Mechanisms regulating T-cell infiltration and activity in solid tumors

Lanitis, Evripidis; Dangaj, Denarda; Irving, Melita; Coukos, George

doi:10.1093/annonc/mdx238

Cited by 309 publications

(228 citation statements)

References 291 publications

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“…DC process tumor antigens and present antigens to T cells, helping to kill tumor cells. Thus, infiltration of T cells into the tumor site can be explained by exposure and secretion of CRT, and secretion of ATP and HMGB1 by the dying cells, which stimulate DC recruitment into the tumor microenvironment, antigen processing and presentation to T cells which then infiltrate the tumor site 48,49 . Indeed, PKHB1 prompted DAMP exposure and release on T‐ALL cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, infiltration of T cells into the tumor site can be explained by exposure and secretion of CRT, and secretion of ATP and HMGB1 by the dying cells, which stimulate DC recruitment into the tumor microenvironment, antigen processing and presentation to T cells which then infiltrate the tumor site. 48,49 F I G U R E 7 PKHB1 induces high-mobility group box 1 (HMGB1) and ATP release in CEM, MOLT-4 and L5178Y-R cell lines. Cells were treated with PKHB1 at CC 50 and CC 100 for 2 h, then 100 μL supernatant of each sample was taken to measure HMGB1 release by ELISA (A) or ATP release through bioluminescence detection (B).…”

Section: Discussionmentioning

confidence: 99%

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CD47 agonist peptide PKHB1 induces immunogenic cell death in T‐cell acute lymphoblastic leukemia cells

et al. 2018

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T‐cell acute lymphoblastic leukemia (T‐ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed thrombospondin‐1‐derived CD47 agonist peptides and demonstrated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first‐described serum‐stable CD47‐agonist peptide) on CEM and MOLT‐4 human cell lines (T‐ALL) and on one T‐murine tumor lymphoblast cell‐line (L5178Y‐R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non‐tumor cells after CD47 activation. In vivo, we determined that PKHB1‐treatment in mice bearing the L5178Y‐R cell line increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze whether CD47 activation induced immunogenic cell death (ICD), we evaluated damage‐associated molecular patterns (DAMP) exposure (calreticulin, CRT) and release (ATP, heat shock proteins 70 and 90, high‐mobility group box 1, CRT). Furthermore, we gave prophylactic antitumor vaccination, determining immunological memory. Our data indicate that PKHB1 induces caspase‐independent and calcium‐dependent cell death in leukemic cells while sparing non‐tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMP release in vitro, and prophylactic vaccinations inhibit tumor establishment in vivo. Together, our results improve the knowledge of CD47 agonist peptides potential as therapeutic tools to treat leukemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CD47 agonist peptide PKHB1 induces immunogenic cell death in T‐cell acute lymphoblastic leukemia cells

et al. 2018

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“…3d, OR = 4.52, P = 2.51E − 57, twosided Fisher's exact test). CD8 T-cell infiltration has been demonstrated to be a useful biomarker for prediction prognosis and response to therapy 31,32 . The identification of these immunerelated lncRNAs provides insight into molecular mechanisms regulating T-cell infiltration and activity in tumors.…”

Section: Identification Of Immune-related Lncrnas Across Cancer Typesmentioning

confidence: 99%

Pan-cancer characterization of immune-related lncRNAs identifies potential oncogenic biomarkers

et al. 2020

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Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and they play fundamental roles in immune regulation. Here we introduce an integrated algorithm, ImmLnc, for identifying lncRNA regulators of immune-related pathways. We comprehensively chart the landscape of lncRNA regulation in the immunome across 33 cancer types and show that cancers with similar tissue origin are likely to share lncRNA immune regulators. Moreover, the immune-related lncRNAs are likely to show expression perturbation in cancer and are significantly correlated with immune cell infiltration. ImmLnc can help prioritize cancer-related lncRNAs and further identify three molecular subtypes (proliferative, intermediate, and immunological) of non-small cell lung cancer. These subtypes are characterized by differences in mutation burden, immune cell infiltration, expression of immunomodulatory genes, response to chemotherapy, and prognosis. In summary, the ImmLnc pipeline and the resulting data serve as a valuable resource for understanding lncRNA function and to advance identification of immunotherapy targets.

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“…In order for this to happen, T-lymphocytes must be able to infiltrate the tumor and mount appropriate responses (5) and higher numbers of CD3+, CD8+ and FOXP3+ tumor infiltrating lymphocytes (TILs) are associated with a favorable outcome in in several malignancies, including HNSCC (6). In particular, the presence of CD8+ “effector” T-cells and the ratio between CD8+ and FOXP3+ regulatory T-cells (Tregs) correlates with improved prognosis.…”

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confidence: 99%

Immune Checkpoint Inhibition in Head and Neck Cancer

2018

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Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common cancer globally and commonly presents with locally advanced disease, which has a recurrence rate of around 50% despite aggressive multi-modality treatment involving surgery, radiotherapy and chemotherapy or EGFR inhibition where appropriate. As understanding of the underlying cancer biology and the complex interactions within the tumor microenvironment improves, there is gathering interest in and evidence for the role of immunomodulating agents in the management of HNSCC. Immune checkpoint inhibitors, which aim to hinder the inhibitory interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1, have demonstrated durable improvements in patient outcomes in advanced / metastatic HNSCC, with both pembrolizumab and nivolumab being granted FDA approval in 2016. There are numerous ongoing clinical trials exploring the role of checkpoint inhibitors both as single agents and in combination, administered with established treatment modalities such as chemotherapy and radiotherapy, as well as alongside other novel immune modulators. These trials are not limited to advanced / metastatic HNSCC, but also to the neo-adjuvant or adjuvant settings. As studies complete and more results become available, the role immunotherapy agents will have within the treatment strategies for HNSCC may change, with increasing biomarker selection resulting in personalized therapy aiming to further improve patient outcomes.

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Mechanisms regulating T-cell infiltration and activity in solid tumors

Cited by 309 publications

References 291 publications

CD47 agonist peptide PKHB1 induces immunogenic cell death in T‐cell acute lymphoblastic leukemia cells

CD47 agonist peptide PKHB1 induces immunogenic cell death in T‐cell acute lymphoblastic leukemia cells

Pan-cancer characterization of immune-related lncRNAs identifies potential oncogenic biomarkers

Immune Checkpoint Inhibition in Head and Neck Cancer

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