Abstract
Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.
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All the data are available under reasonable request. Material requests should be addressed to satoshi7@med.niigata-u.ac.jp.
Abbreviations
- CAR-T:
-
Chimeric antigen receptor T
- DCs:
-
Dendritic cells
- Foxp3:
-
Forkhead box P3
- i.v:
-
Intravenous
- i.p:
-
Intraperitoneally
- ICIs:
-
Immune checkpoint inhibitors
- mAbs:
-
Monoclonal antibodies
- MDSCs:
-
Myeloid-derived suppressor cells
- PD-1:
-
Programmed-cell death-1
- PD-L1:
-
PD-ligand 1
- s.c:
-
Subcutaneous
- TDLNs:
-
Tumor-draining lymph nodes
- TILs:
-
Tumor-infiltrating lymphocytes
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Funding
This work was supported by the Japan Society for Promotion of Science KAKENHI Grant Number 24591157 (to S. Watanabe).
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SW, QZ, BH and LD designed experiments. MT, RS, MA, MS, YS, YA, FS, and SH performed experiments. MT, SW, and KS acquired data. SW and YS analyzed data and generated figures. MT and SW wrote the manuscript. AO, SS, and KN supervised the analysis. KI, RK, NA, YO, MH, TK, and TK discussed the results and conclusions and commented on the manuscript at all stages. All authors read and approved the final manuscript.
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All animal studies were approved by the Niigata University Institutional Animal Care and Use Committee.
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262_2021_3078_MOESM1_ESM.pdf
Expression of checkpoint receptors after lymphodepletion and T cell transfer.B6 mice were inoculated s.c. with B16F10 tumor cells. These mice were irradiated and reconstituted with spleen cells from Ly5.1 mice 7 days after tumor inoculation or injected i.p. with anti-PD-1 mAb (250 μg per mouse) on days 7 and 14. Tumor tissues were harvested and prepared for FACS analysis on day 21. A-L, The percentage of PD-L1+, PD-1+, TIGIT+, ICOS+, TIM-3+, LAG-3+cells among CD4+T cells are shown. B-L, The percentage of PD-L1+, PD-1+, TIGIT+, ICOS+, TIM-3+, LAG-3+cells among CD8+T cells are presented. Data are shown as mean ± SE (n = 3/group). P values were estimated with the Student’s t test and are shown as *p < 0.05, **p < 0.01 or ***p < 0.001 (PDF 264 KB)
262_2021_3078_MOESM2_ESM.pdf
Expression of checkpoint receptors after lymphodepletion and the transfer of T cells from irradiated hosts.B6 mice were inoculated s.c. with MCA205 tumor cells. These mice were irradiated and reconstituted with spleen cells from Ly5.1 mice 7 days after tumor inoculation or injected i.p. with anti-PD-1 mAb (250 μg per mouse) on days 7 and 14. Donor Ly5.1 mice were irradiated 14 days before the harvest of spleens. Tumor tissues were harvested and prepared for FACS analysis on day 21. A-L, The percentage of PD-L1+, PD-1+, TIGIT+, ICOS+, TIM-3+, LAG-3+cells among CD4+T cells are shown. B-L, The percentage of PD-L1+, PD-1+, TIGIT+, ICOS+, TIM-3+, LAG-3+cells among CD8+T cells are presented. Data are shown as mean ± SE (n = 3/group). P values were estimated with the Student’s t test and are shown as *p < 0.05, **p < 0.01 or ***p < 0.001 (PDF 324 KB)
262_2021_3078_MOESM3_ESM.pdf
Expression of checkpoint receptors in tumor-draining lymph node cells after lymphodepletion and the transfer of T cells.B6 mice were inoculated s.c. with MCA205 tumor cells. These mice were irradiated and reconstituted with spleen cells from Ly5.1 mice 7 days after tumor inoculation or injected i.p. with anti-PD-1 mAb (250 μg per mouse) on days 7 and 14. Tumor-draining lymph nodes were harvested and prepared for FACS analysis on day 21. A-L,The percentage of PD-L1+, PD-1+, TIGIT+, ICOS+, TIM-3+, LAG-3+cells among CD4+T cells are shown. B-L, The percentage of PD-L1+, PD-1+, TIGIT+, ICOS+, TIM-3+, LAG-3+cells among CD8+T cells are presented. Data are shown as mean ± SE (n = 3/group). P values were estimated with the Student’s t test and are shown as *p < 0.05 or **p < 0.01 (PDF 302 KB)
262_2021_3078_MOESM4_ESM.pdf
The combination of lymphodepletion, T cell transfer, anti-PD-1 Abs, and anti-CD25 Abs for advanced skin tumor model. MCA205 tumor-bearing mice were irradiated and adoptively transferred naïve T cells 20 days after tumor inoculation. The mice were treated with anti-CD25 mAbs to deplete Tregs on day 20 and received anti-PD-1 treatment on days 20, 26, and 32. P value was estimated with the Student’s t test (PDF 113 KB)
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Takahashi, M., Watanabe, S., Suzuki, R. et al. PD-1 blockade therapy augments the antitumor effects of lymphodepletion and adoptive T cell transfer. Cancer Immunol Immunother 71, 1357–1369 (2022). https://doi.org/10.1007/s00262-021-03078-0
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DOI: https://doi.org/10.1007/s00262-021-03078-0