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Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion
David H Peng1, Bertha Leticia Rodriguez1, Lixia Diao2
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Abstract:
Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.
Insights
Tumor collagen promotes T cell exhaustion and resistance to immunotherapy (PD-1/PD-L1 blockade). Targeting collagen or its associated pathways (LAIR1) can restore anti-tumor immunity and improve patient response.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Tumor extracellular matrix components, like collagen, are implicated in drug resistance and immune suppression.
- Resistance to PD-1/PD-L1 blockade is a significant clinical challenge in cancer therapy.
Purpose of the Study:
- To investigate the role of tumor collagen in resistance to PD-1/PD-L1 blockade.
- To identify mechanisms and therapeutic targets for overcoming immunotherapy resistance.
Main Methods:
- Proteomic and RNA profiling of lung tumors.
- Analysis of murine and human lung tumor samples.
- Assessment of T cell populations and exhaustion markers.
- In vivo studies involving LOXL2 suppression and LAIR1 modulation.
- Clinical correlation analysis in melanoma patients.
Main Results:
- Increased collagen levels in tumors resistant to PD-1/PD-L1 blockade.
- Collagen correlates with reduced CD8+ T cells and increased T cell exhaustion via the LAIR1-SHP-1 axis.
- LOXL2 suppression or LAIR1 pathway inhibition sensitizes tumors to immunotherapy.
- Elevated collagen, LAIR1, and TIM-3 predict poor survival in melanoma patients.
Conclusions:
- Tumor collagen and the LAIR1 pathway are key drivers of immunotherapy resistance.
- Targeting collagen deposition or LAIR1 signaling presents promising therapeutic strategies.
- Collagen and LAIR1 serve as potential biomarkers for predicting immunotherapy response.
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