%0 Journal Article
%T Loss of CXCL12 Drives Colorectal Cancer Progression and Impairs Anti-PD-L1 Immunotherapy via MDSC Modulation
%A Natalie Rose Bennett
%A Oliver James King
%A Julien Marc Lefevre
%A Antoine Pascal Durand
%J Journal of Medical Sciences and Interdisciplinary Research
%@ 3108-4826
%D 2022
%V 2
%N 1
%R 10.51847/c2qR6ArN0J
%P 154-175
%X Numerous approaches targeting the CXCL12 pathway, particularly CXCR4 inhibitors, have been explored for treating colorectal cancer (CRC). Although these methods have demonstrated partial success in clinical studies, the reasons why reduced CXCL12 levels impair the effectiveness of anti-PD-L1 therapy—a major obstacle in immunotherapy—remain poorly understood, underscoring the necessity for further mechanistic investigation and improved therapeutic approaches. This research combined single-cell transcriptomic sequencing, in vitro cellular assays, and in vivo animal models to detect CXCL12-associated RNA-binding proteins (RBPs) with causal connections to CRC, pinpoint critical cell populations involved in resistance, and confirm underlying mechanisms. Twelve RBPs linked to CXCL12 exhibited causal associations with CRC. Using machine learning techniques and diagnostic evaluations, CPEB3, DDX39B, and SIDT2 emerged as potential CRC biomarkers. Monocytes were identified as the primary cell type in CRC due to their expression patterns of these biomarkers. Single-cell transcription factor profiling revealed two key CRC-associated factors: MEIS2 and TCF4. Both in vitro and in vivo experiments demonstrated that silencing CXCL12 enhanced the migratory and invasive abilities of CRC cells. Significantly, combining CXCL12 overexpression with PD-L1 blockade resulted in the greatest reduction in cell viability and invasiveness, suggesting that CXCL12 potentiates rather than hinders anti-PD-L1 treatment efficacy. Additionally, CXCL12 levels showed a negative correlation with the abundance and quantity of myeloid-derived suppressor cells. The discovery of CPEB3, DDX39B, and SIDT2 as biomarkers tied to CXCL12 in CRC, along with evidence connecting CXCL12 to MDSC modulation and resistance to anti-PD-L1 therapy, offers a new perspective on immunotherapy failure in CRC. These insights could inform the design of clinical treatment protocols and support the creation of CXCL12-based combination therapies to surmount anti-PD-L1 resistance and enhance immunotherapy results in CRC.
%U https://smerpub.com/article/loss-of-cxcl12-drives-colorectal-cancer-progression-and-impairs-anti-pd-l1-immunotherapy-via-mdsc-mo-6amzaiuqihjt7zf