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| Status |
Public on Mar 04, 2024 |
| Title |
Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
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| Overall design |
The CT26 mouse colon carcinoma cell line was obtained from American Type Culture Collection. A total of 100,000 CT26 cells was inoculated subcutaneously into the right unilateral flank of the syngeneic BALB/c mice. All mice used were 6-8 week old and female. After approximately 10–12 days, mice bearing tumours of 150–200 mm3 were randomized into treatment groups on the basis of tumour size and treated with anti-mouse PD-L1 (6E11, isotype IgG2a LALAPG, 10 mg per kg), anti-mouse TIGIT (10A7, isotypes IgG2a, mIgG2b, and IgG2a LALAPG, 10 mg per kg), anti-mouse CSF-1R (Bioexcell, BP0213, 30 mg per kg) and/or anti-gp120 control antibodies (IgG2a isotype, to total 35 mg per kg overall antibody dosing). Antibodies were administered once intravenously, and 72 h after treatment, mice were euthanized by asphyxiation and CD45+ cells were collected for scRNA-seq analysis.
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| Web link |
https://www.nature.com/articles/s41586-024-07121-9
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| Contributor(s) |
Guan X, Hu R, Choi Y, Srivats S, Nabet BY, Silva J, McGinnis L, Hendricks R, Nutsch K, Banta KL, Duong E, Dunkle A, Chang PS, Han C, Mittman S, Molden N, Daggumati P, Connolly W, Johnson M, Abreu D, Cho B, Italiano A, Gil-Bazo I, Felip E, Mellman I, Mariathasan S, Shames DS, Meng R, Chiang EY, Johnston RJ, Patil NS |
| Citation(s) |
38418879, 39164390 |
| BioProject |
PRJNA1082777 |
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| Submission date |
Mar 04, 2024 |
| Last update date |
Oct 09, 2024 |
| Contact name |
Xiangnan Guan |
| E-mail(s) |
guanx8@gene.com
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| Organization name |
Genentech
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| Street address |
1 DNA WAY
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| City |
South San Francisco |
| State/province |
California |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (46)
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| GSM8124966 |
blood_ctrl_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124967 |
blood_ctrl_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124968 |
blood_tigitlalapg_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124969 |
blood_tigitlalapg_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124970 |
blood_tigit2b_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124971 |
blood_tigit2b_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124972 |
blood_tigit2a_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124973 |
blood_tigit2a_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124974 |
tumor_ctrl_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124975 |
tumor_ctrl_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124976 |
tumor_tigitlalapg_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124977 |
tumor_tigitlalapg_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124978 |
tumor_tigit2b_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124979 |
tumor_tigit2b_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124980 |
tumor_tigit2a_ADT_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124981 |
tumor_tigit2a_mRNA_EXP_anti_TIGIT_monoTx_batch1 |
| GSM8124982 |
blood_ctrl_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124983 |
blood_ctrl_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124984 |
blood_PDL1_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124985 |
blood_PDL1_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124986 |
blood_tigit2b_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124987 |
blood_tigit2b_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124988 |
blood_tigit2a_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124989 |
blood_tigit2a_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124990 |
blood_PDL1tg2b_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124991 |
blood_PDL1tg2b_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124992 |
blood_PDL1tg2a_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124993 |
blood_PDL1tg2a_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124994 |
tumor_ctrl_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124995 |
tumor_ctrl_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124996 |
tumor_PDL1_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124997 |
tumor_PDL1_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124998 |
tumor_tigit2b_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8124999 |
tumor_tigit2b_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8125000 |
tumor_tigit2a_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8125001 |
tumor_tigit2a_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8125002 |
tumor_PDL1tg2b_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8125003 |
tumor_PDL1tg2b_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8125004 |
tumor_PDL1tg2a_ADT_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8125005 |
tumor_PDL1tg2a_mRNA_EXP_anti_TIGIT_comboTx_batch2 |
| GSM8125006 |
tumor_IgG2a_ADT_EXP_anti_CSF1R_batch3.1 |
| GSM8125007 |
tumor_IgG2a_mRNA_EXP_anti_CSF1R_batch3.1 |
| GSM8125008 |
tumor_PT_ADT_EXP_anti_CSF1R_batch3.1 |
| GSM8125009 |
tumor_PT_mRNA_EXP_anti_CSF1R_batch3.1 |
| GSM8125010 |
tumor_PT_antiCSF1R_ADT_EXP_anti_CSF1R_batch3.1 |
| GSM8125011 |
tumor_PT_antiCSF1R_mRNA_EXP_anti_CSF1R_batch3.1 |
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| Supplementary file |
Size |
Download |
File type/resource |
| GSE260816_feature_reference.csv.gz |
207 b |
(ftp)(http) |
CSV |
| GSE260816_mouse_scSeq_anti-CSF1R_tumor_T_NK_RNA_raw_counts.rds.gz |
112.7 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-CSF1R_tumor_T_NK_metadata.rds.gz |
745.8 Kb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-CSF1R_tumor_myeloid_RNA_raw_counts.rds.gz |
16.9 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-CSF1R_tumor_myeloid_metadata.rds.gz |
141.4 Kb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_comboTx_blood_RNA_raw_counts.rds.gz |
232.9 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_comboTx_blood_metadata.rds.gz |
2.1 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_comboTx_tumor_T_NK_RNA_raw_counts.rds.gz |
199.6 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_comboTx_tumor_T_NK_metadata.rds.gz |
1.4 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_comboTx_tumor_myeloid_RNA_raw_counts.rds.gz |
18.0 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_comboTx_tumor_myeloid_metadata.rds.gz |
185.5 Kb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_monoTx_blood_RNA_raw_counts.rds.gz |
93.9 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_monoTx_blood_metadata.rds.gz |
879.4 Kb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_monoTx_tumor_T_NK_RNA_raw_counts.rds.gz |
112.2 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_monoTx_tumor_T_NK_metadata.rds.gz |
863.6 Kb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_monoTx_tumor_myeloid_RNA_raw_counts.rds.gz |
28.6 Mb |
(ftp)(http) |
RDS |
| GSE260816_mouse_scSeq_anti-TIGIT_monoTx_tumor_myeloid_metadata.rds.gz |
231.9 Kb |
(ftp)(http) |
RDS |
| GSE260816_readme.txt |
610 b |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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