Accelerated elimination of human cancer cells by a CD40 agonist antibody combined with a PD‑1 antagonist in CD4‑depleted mice

Ahn, Sang Hyun; Choi, Joo Yeon; Kim, Seong Dong; Park, Sung‐Joon; Kim, Hyojin

doi:10.3892/ol.2019.10991

Cited by 3 publications

(3 citation statements)

References 16 publications

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“… 45 In addition, it was reported that TNFRSF5 (CD40) agonists could reverse resistance to anti-PD-1 therapy. 46 , 47 Therefore, TNF-related axes seem to play a role in immunotherapy. To our surprise, in our study, we found that TNF-TNFRSF1A and TNF-FAS interactions between CD8 T cells/macrophages/tumor cells and other cells were consistently weaker in nonresponders than in responders, while the TNFSF10/MIF-TNFRSF10D interactions between other cells and endothelial cells and the TNFSF13-related ligand-receptor interactions between pDCs/macrophages and other cells were consistently weaker in responders than in nonresponders.…”

Section: Discussionmentioning

confidence: 99%

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data

et al. 2021

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Currently, a significant proportion of cancer patients do not benefit from programmed cell death-1 (PD-1)-targeted therapy. Overcoming drug resistance remains a challenge. In this study, single-cell RNA sequencing and bulk RNA sequencing data from samples collected before and after anti-PD-1 therapy were analyzed. Cell-cell interaction analyses were performed to determine the differences between pretreatment responders and nonresponders and the relative differences in changes from pretreatment to posttreatment status between responders and nonresponders to ultimately investigate the specific mechanisms underlying response and resistance to anti-PD-1 therapy. Bulk-RNA sequencing data were used to validate our results. Furthermore, we analyzed the evolutionary trajectory of ligands/receptors in specific cell types in responders and nonresponders. Based on pretreatment data from responders and nonresponders, we identified several different cell-cell interactions, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Furthermore, relative differences in the changes from pretreatment to posttreatment status between responders and nonresponders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. In trajectory analyses of tumor-specific exhausted CD8 T cells using ligand/receptor genes, we identified a cluster of T cells that presented a distinct pattern of ligand/receptor expression. They highly expressed suppressive genes like HAVCR2 and KLRC1, cytotoxic genes like GZMB and FASLG and the tissue-residence-related gene CCL5. These cells had increased expression of survival-related and tissue-residence-related genes, like heat shock protein genes and the interleukin-7 receptor (IL-7R), CACYBP and IFITM3 genes, after anti-PD-1 therapy. These results reveal the mechanisms underlying anti-PD-1 therapy response and offer abundant clues for potential strategies to improve immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data

et al. 2021

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“…According to this theory, cancer recurrence is not only dependent on the tumorigenic potential of cancer cells but also on the relationship between cancer cells and the immunity of patients. A previous study by our laboratory has shown that decreased expression of CD40L in regional cancer-free lymph nodes is a significant poor prognostic factor (2) and that depletion of CD4 in immunocompetent mice delays the clearance of injected human cancer cells in the tongue (3). These data suggest that the CD40-CD40L interaction can be an important target to improve treatment outcome.…”

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confidence: 63%

Adjuvant Postoperative CD40 Agonist and PD-1 Antagonist Combination Therapy in Syngeneic Tongue Cancer Mouse Model

Ahn

Song

2020

Anticancer Res

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Background/Aim: Using a syngeneic tongue cancer mouse model, the effect of CD40 agonist and PD-1 antagonist combination therapy for local recurrence after surgery was evaluated in a partially depleted CD4 model. Materials and Methods: C3H/HeN mice were injected with 0.05 mg of the anti-mouse CD4 clone GK1.5, causing partial depletion of CD4 cells. Tongue cancer was induced by injecting the squamous cell carcinoma (SCC) VII cell line, the tumor was resected by partial glossectomy, and CD40 agonist and/or PD-1 antagonist therapy was administered postoperatively. Results: Partial depletion of CD4 cells resulted in faster growth of a recurring tumor in the tongue, faster loss of body weight, and decreased number of CD8apositive cells in the tumor. Postoperative adjuvant therapy with a combination of CD40 agonist and PD-1 antagonist resulted in a significant increase in survival compared to the CD40 agonist single treatment. Conclusion: CD40 agonist and PD-1 antagonist combination therapy could be an effective postoperative adjuvant treatment, especially in cases with decreased CD4 T cell activity.

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“…Another proposed mechanism of turning 'cold' tumors 'hot' is via CD40 activation using agonist CD40 antibodies [337,375,376]. Long-term clinical responses have been reported in a Phase I trial of tremelimumab + CP-870893 (CD40 agonist) in ICI-naive melanoma [337].…”

Section: Icis Plus Tgf-β Inhibitorsmentioning

confidence: 99%

Addressing Resistance to Immune Checkpoint Inhibitor Therapy: An Urgent Unmet Need

et al. 2021

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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various cancers by reversing the immunosuppressive mechanisms employed by tumors to restore anticancer immunity. Although ICIs have demonstrated substantial clinical efficacy, patient response can vary in depth and duration, and many do not respond at all or eventually develop resistance. ICI resistance mechanisms can be tumor-intrinsic, related to the tumor microenvironment or patient-specific factors. Multiple resistance mechanisms may be present within one tumor subtype, or heterogeneity exists among patients with the same tumor type. Consequently, designing effective combination treatment strategies is challenging. This review will discuss ICI resistance mechanisms, and summarize findings from key preclinical and clinical trials of ICIs, to identify potential treatment strategies or pathways to overcome ICI resistance.

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Accelerated elimination of human cancer cells by a CD40 agonist antibody combined with a PD‑1 antagonist in CD4‑depleted mice

Cited by 3 publications

References 16 publications

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data

Adjuvant Postoperative CD40 Agonist and PD-1 Antagonist Combination Therapy in Syngeneic Tongue Cancer Mouse Model

Addressing Resistance to Immune Checkpoint Inhibitor Therapy: An Urgent Unmet Need

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