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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 (human) |
| Organism |
Homo sapiens |
| 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 |
Dendritic cells were derived from monocytes, which were purified from PBMCs using a human pan monocyte isolation kit (Miltenyi). DCs were generated by culturing monocytes in X-VIVO 15 media (Lonza) containing 50 ng/mL recombinant human GM-CSF (Peprotech) and 50 ng/mL recombinant human IL-4 (Peprotech) for 5-6 days. 96-well tissue culture plates (Corning) were coated with 5 µg/mL human collagen type 1 (Millipore Sigma) in PBS overnight at 4° C, then washed in PBS. 1 x 105 DCs were added to the plates with anti-LAIR1 or an isotype control antibody at the listed concentrations then incubated for 2 days at 37° C. Conditioned media was collected the next day and analyzed using Luminex (ProcartaPlex, ThermoFisher).
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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) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (6)
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| GSM8120447 |
control isotype antibody treatment on collagen from patient 20356, sample 55 |
| GSM8120448 |
control isotype antibody treatment on collagen from patient 30214, sample 47 |
| GSM8120449 |
control isotype antibody treatment on collagen from patient 20961, sample 51 |
| GSM8120450 |
47H1 treatment on collagen from patient 30214, sample 54 |
| GSM8120451 |
47H1 treatment on collagen from patient 20961, sample 50 |
| GSM8120452 |
47H1 treatment on collagen from patient 30214, sample 46 |
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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 |
PRJNA1082305 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE260597_allSamples_Genes_ReadCounts.txt.gz |
291.4 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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