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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Mar 04, 2024 |
| Title |
Anti-tumor activity of a novelLAIR1antagonist in combination with anti-PD-1to treat collagen-rich solid tumors (mouse) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
We recently reported that resistance to PD-1-blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), and thus we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. Here, we report LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist monoclonal antibody, elicits myeloid inflammation and allogeneic T cell responses by binding to LAIR1 and blocking collagen engagement. Further, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.
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| Overall design |
The murine lung cancer cell line 344SQ was derived from K-rasLA1/+p53R172H∆g/+ mice. 6-8 week old 129/Sv mice were obtained from Charles River Laboratories. For studying the tumor growth in syngeneic immunocompetent models, 344SQ cells (1x106) were implanted subcutaneously into the right flank of male and female mice. When tumors reached an average size of 50-100 mm3 anti-LAIR was dosed 10 mg/kg I.P. twice per week and/or anti-PD-1 (Bioxcell) was dosed 8 mg/kg once per week. Tumor growth was measured with digital calipers once a week, and tumor sizes were calculated using the formula: ½(length × width × width) at indicated time points. At end points, mice were sacrificed to examine the tumor weight and metastatic lung nodules. GEMM (KrasLSL-G12D/p53fl/fl) were generated as previously described (47,49). Mice were infected at 3-4 months of age with 2.5x107 titer pfu adenovirus-cre by intratracheal intubation. Treatment with antibodies were performed at 2 months post-infections when tumors were visualized by micro-CT imaging. All mice were immunocompetent and assessed for health daily by the department of veterinary medicine and surgery at The University of Texas MD Anderson Cancer Center. All animal procedures were reviewed and approved by The University of Texas MD Anderson Cancer Center Animal Care and Use Committee.
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| Contributor(s) |
Rodriguez BL, Huang J, Gibson L, Fradette J, Chen H, Koyano K, Cortez C, Li B, Ho C, Ashique A, Lin V, Crawley S, Roda J, Chen P, Fan B, Kim J, Sissons J, Sitrin J, Kaplan D, Gibbons D, Rivera L |
| Citation(s) |
38648067 |
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| Submission date |
Feb 29, 2024 |
| Last update date |
Aug 07, 2024 |
| Contact name |
Lee Benjamin Rivera |
| E-mail(s) |
lrivera@ngmbio.com
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| Organization name |
NGM Bio
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| Department |
Biology
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| Street address |
333 Oyster Point Blvd.
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| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (7)
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| GSM8120440 |
anti-PD-1 + control anti-KLH treatment at Week 4, mouse LOHM_a |
| GSM8120441 |
anti-PD-1 + control anti-KLH treatment at Week 4, mouse KWM_a |
| GSM8120442 |
anti-PD-1 + control anti-KLH treatment at Week 4, mouse LOHM_d |
| GSM8120443 |
anti-PD-1 + anti-Lair1 treatment at Week 4, mouse WTSV_ai |
| GSM8120444 |
anti-PD-1 + anti-Lair1 treatment at Week 4, mouse WTSV_ae |
| GSM8120445 |
anti-PD-1 + anti-Lair1 treatment at Week 4, mouse WTSV_af |
| GSM8120446 |
anti-PD-1 + anti-Lair1 treatment at Week 4, mouse WTSV_ah |
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| This SubSeries is part of SuperSeries: |
| GSE260599 |
Anti-tumor activity of a novelLAIR1antagonist in combination with anti-PD-1to treat collagen-rich solid tumors |
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| Relations |
| BioProject |
PRJNA1082304 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE260596_AllSamples_Genes_ReadCounts.txt.gz |
306.1 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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