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Targeting glycan sulfation in a CD11c+ myeloid population inhibits early KRAS-mutant lung neoplasia1☆☆☆
Targeting glycan sulfation in a CD11c+ myeloid population inhibits early KRAS-mutant lung neoplasia1☆☆☆
- Source :
- Neoplasia (New York, N.Y.)
- Publication Year :
- 2021
- Publisher :
- Neoplasia Press, 2021.
-
Abstract
- Early lung carcinoma development may be modulated by innate host cellular mechanisms that promote tumor growth and invasion. We recently identified how a loss-of-function mutation in the glycan sulfating enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in heparan sulfate biosynthesis) targeted to antigen presenting cells (APCs) may augment acquired anti-tumor T cell immune mechanisms. Crossing this mutation (Ndst1f/f CD11cCre+) onto a model of inducible spontaneous Kras mutant lung cancer [CCSP-rtTA; (tetO7) CMV-Kras-G12D] allowed us to examine how the APC mutation affects the formation and growth of early lung carcinoma. We examined early bronchocentric adenoma formation in the model, and the frequency of such events was significantly reduced on the mutant background. This was associated with significant reductions in tumor associated FOXP3+ cellular infiltration and CD163+ M2-type macrophage infiltration. The findings evolved prior to effector CD8+ T cell infiltration into tumors. The impact of this unique glycan under-sulfating mutation on inhibiting early Kras G12D mutant bronchocentric adenoma formation along with a cellular phenotype of inhibited tumor infiltration by cells involved in suppressive T-regulatory cell signaling (FOXP3+ cells) or tumor-permissive M2 macrophage functions (CD163+ cells) provides insight on how glycan targeting may modulate innate cellular mechanisms during early lung tumor development. The findings may also impact the future design of host-centered immunologic anti-tumor therapeutic strategies.
- Subjects :
- Adenoma
tumor
IHC, Immunohistochemistry
Doxy, doxycycline
Lung Neoplasms
Macrophage
Short Communication
Heparan sulfate
Mice, Transgenic
CD8-Positive T-Lymphocytes
T-Lymphocytes, Regulatory
Proto-Oncogene Proteins p21(ras)
TAM, Tumor associated macrophage
Mice
Lymphocytes, Tumor-Infiltrating
HS, Heparan sulfate
Polysaccharides
CD11c, CD11c locus
Animals
Humans
HSPG, Heparan sulfate proteoglycan
Myeloid Cells
ICI, Immune checkpoint inhibition
Cancer
MHC, Major histocompatibility complex
Sulfates
T cell
Treg, Regulatory T cell
DC, Dendritic cell
CD11c Antigen
Mice, Inbred C57BL
APCs, Antigen presenting cells
Ndst, N-deacetylase/N-sulfotransferase
Mutation
Kras
LLC, Lewis lung carcinoma
BSA, Bovine Serum Albumin
Heparitin Sulfate
Sulfotransferases
TTBS, Tween tris buffered saline
Subjects
Details
- Language :
- English
- ISSN :
- 14765586 and 15228002
- Volume :
- 23
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Neoplasia (New York, N.Y.)
- Accession number :
- edsair.pmid..........6c1a8c4e83557920ae120f81f6685b95