Targeting glycan sulfation in a CD11c+ myeloid population inhibits early KRAS-mutant lung neoplasia.

Neoplasia

VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA, USA; Department of Medicine, Division of Pulmonary and Critical Care, University of California San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA, USA; Veterans Medical Research Foundation, San Diego, CA, USA. Electronic address:

Published: November 2021

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560828PMC
http://dx.doi.org/10.1016/j.neo.2021.09.008DOI Listing

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