The Potential Role Of Leukocyte-Associated Immunoglobulin-Like Receptor 2 In Esophageal Cancer

Esophageal squamous-cell carcinoma(ESCC),one of the most commonly diagnosed and lethal malignant diseases,has a complex tumor ecosystem.An obvious requirement for T cell-mediated tumor control is the infiltration of tumor reactive T cells into the tumor.In the present study,we have performed scRNA-seq(Single cell RNA sequencing,scRNA-seq)in T cells from ESCC tumor and matched PBMCs(Peripheral blood mononuclear cell,PBMCs)respectively and deciphered the molecular state and compositions of T cell sub-clusters.Specifically,we noted that ESCC tumors were significantly enriched in exhausted T cells(C0-CD8-Tex),proliferating T cells(C14-CD8-STMN1)and Treg cells(Regulatory cells)(C7-Tregs).However,PBMCs were significantly enriched in cytotoxic(C3-CD8-FGFBP2 and C11-CD8-KLRG1)and na?ve T cells.We found that LAIR2(Leukocyte-associated immunoglobulin like receptor 2)was differently expressed in PBMCs and tumors.LAIR2 is a secreted receptor that shares a similar extracellular domain with LAIR1(Leukocyte-associated immunoglobulin like receptor 1),a collagen-receptor that inhibits immune cell function through SHP-1(Src-homology domain-2 containing protein tyrosine phos-phatase-1)signaling upon collagen binding.In our data,LAIR2 had higher transcripts abundance than LAIR1 and exhibited specific expression profiles in T cell subtypes.The immunosuppressive function of LAIR1 is well-studied,the role of LAIR2 in solid tumor is poorly defined and needs further investigation.Our in vitro experiments showed that LAIR2 inhibited tumor metastasis but had no effect on tumor growth or proliferation,however could significantly inhibit tumor cell metastasis and invasion via suppressing the phosphorylation of both Smad3 and AKT,indicating that LAIR2 could inhibit both Smad-dependent and non-dependent TGF-beta(Transforming growth factor-β)signaling activation,thereby inhibiting TGF-β induced EMT(Epithelial-Mesenchymal transition).In addition,we demonstrated that LAIR2 treatment educed F-actin and type 1 collagen in ESCC tumor cells,thereby inhibiting the tumor cell metastasis.Co-culture experiment showed that LAIR2 also down-regulated the percentage of PD-1+TIM-3+CD8+exhausted T cells in of PBMCs,and PD-L1 expressions of tumor cells.In our in vivo study,administration of LAIR2 protein could significantly down-regulate ESCC tumor metastasis,suppressing collagen deposition and PD-L1 expression of lung tissue in the ESCC metastasis model.In summary,our transcriptional map of T cells from ESCC tumor and matched PBMCs provided a picture for understanding the immune status,illustrating LAIR2 expression pattern and function from many aspects,which are essential for developing immunotherapies in ESCC.