Targeting late-stage non-small cell lung cancer with a combination of DNT cellular therapy and PD-1 checkpoint
Linan Fang1,2, Dalam Ly2,3, Si-Si Wang4
1Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China.
Background:
Though immune checkpoint blockade (ICB) against PD-1 has shown success in the treatment of lung cancer, not all patients respond. We have previously shown that adoptive transfer of double negative T (DNT) cells expanded from healthy donors can target leukemia but their role in treating established lung cancer is not clear. Here we explore the role of human DNT cells in targeting late-stage established lung cancer either alone or in combination with Nivolumab (anti-PD-1 antibody) and describe underlying mechanisms.
Methods:
DNT cells from resected lung cancer tissue of patients were analyzed by flow cytometry to determine their infiltration and PD-1 expression. Expansion capacity and anti-tumor function of lung cancer patient and healthy donor DNT cells were compared. Late-stage lung cancer xenograft models were developed to determine the anti-tumor effect of DNT cells alone or in combination with anti-PD-1 antibody, and the level of tumor-infiltrating DNT cells was quantified by histology and characterized by flow cytometry.
Results:
Patient-derived tumor infiltrating lymphocytes contained a lower frequency of DNT cells with a higher expression of PD-1 relative to normal lung tissue. Ex vivo expanded patient- and healthy donor-derived DNT cells showed similar levels of cytotoxicity against lung cancer cells in vitro. Healthy donor-derived DNT cells significantly inhibited the growth of late-stage lung cancer xenografts, which was further augmented by anti-PD-1 through increased DNT cell tumor infiltration.
Conclusion:
This study supports the use of DNT cells for adoptive cellular therapy against lung cancer either alone or in combination with anti-PD-1.
Insights
Double negative T (DNT) cells show promise for treating lung cancer. Combining DNT cell therapy with anti-PD-1 antibodies enhances their anti-tumor effects in established lung cancer models.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Immune checkpoint blockade (ICB) targeting PD-1 is a successful lung cancer treatment, but response rates vary.
- Previous research demonstrated the efficacy of double negative T (DNT) cell adoptive transfer in leukemia.
- The role of DNT cells in treating established lung cancer remains unclear.
Purpose of the Study:
- To investigate the potential of human DNT cells in targeting late-stage lung cancer.
- To evaluate DNT cells as a monotherapy and in combination with Nivolumab (anti-PD-1 antibody).
- To elucidate the underlying mechanisms of DNT cell activity in lung cancer.
Main Methods:
- Flow cytometry analysis of DNT cell infiltration and PD-1 expression in patient tumor tissues.
- Comparison of expansion capacity and anti-tumor function of DNT cells from patients and healthy donors.
- Assessment of DNT cell efficacy and tumor infiltration in late-stage lung cancer xenograft models, alone and with anti-PD-1.
Main Results:
- Tumor-infiltrating lymphocytes from lung cancer patients had fewer DNT cells with higher PD-1 expression compared to normal lung tissue.
- Expanded DNT cells from both patients and healthy donors exhibited comparable in vitro cytotoxicity against lung cancer cells.
- Healthy donor DNT cells significantly inhibited xenograft tumor growth, an effect amplified by anti-PD-1 via enhanced DNT cell infiltration.
Conclusions:
- DNT cells demonstrate significant anti-tumor activity against established lung cancer xenografts.
- Combination therapy with DNT cells and anti-PD-1 antibody enhances therapeutic efficacy.
- This study supports the clinical application of DNT cells for lung cancer adoptive cellular therapy.
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