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Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer
- Source :
- OncoImmunology, Vol 7, Iss 7 (2018), Oncoimmunology, OncoImmunology, 7(7):e1448332. Landes Bioscience
- Publication Year :
- 2018
-
Abstract
- Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.
- Subjects :
- 0301 basic medicine
lcsh:Immunologic diseases. Allergy
Colorectal cancer
medicine.medical_treatment
T cell
Immunology
immune checkpoint inhibitor
colorectal cancer
lcsh:RC254-282
Metastasis
03 medical and health sciences
0302 clinical medicine
SDG 3 - Good Health and Well-being
tumor-infiltrating lymphocyte
medicine
Immunology and Allergy
neoplasms
Original Research
Tumor-infiltrating lymphocytes
business.industry
pd-1
Immunotherapy
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
t cell
Immune checkpoint
digestive system diseases
lag3
liver metastasis
mismatch repair
030104 developmental biology
Cytokine
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
peritoneal metastasis
Cancer research
DNA mismatch repair
immunotherapy
business
lcsh:RC581-607
Subjects
Details
- Language :
- English
- ISSN :
- 21624011
- Volume :
- 7
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- OncoImmunology
- Accession number :
- edsair.doi.dedup.....e2c2263fee5f55109108bfe1ab00df55