Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment

Abstract

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming.Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

exSSSRs (extracellular S100 soil sensor receptors)‐Fc fusion proteins work as prominent decoys to S100A8/A9‐induced lung tropic cancer metastasis

“…5,6 The relationship between S100A8/A9 and these receptors may be applicable to broad cancer species since S100A8/A9 is also utilized by breast cancer cells for lung tropic metastasis. 7 Since these receptors seem to be differently expressed depending on the cancer species and since their expression seems to be upregulated in response to the progression of cancer malignancy (our study and our ongoing studies), the S100A8/A9-SSSRs axis therefore may act as an important mediator in "seed and soil" metastasis in multiple cancer species. We hence had the idea that the extracellular domains of SSSRs (exSSSRs) function as decoys to prevent binding of S100A8/A9 to endogenous SSSRs of cancer cells when they fuse with the Fc region of IgG.…”

“…We then found further evidence of other important novel soil sensors for S100A8/A9: EMMPRIN, NPTNβ, MCAM and ALCAM . We named the proteins “S100 soil sensor receptors, abbreviated as SSSRs.” The relationship between S100A8/A9 and these receptors may be applicable to broad cancer species since S100A8/A9 is also utilized by breast cancer cells for lung tropic metastasis . Since these receptors seem to be differently expressed depending on the cancer species and since their expression seems to be upregulated in response to the progression of cancer malignancy (our study and our ongoing studies), the S100A8/A9‐SSSRs axis therefore may act as an important mediator in “seed and soil” metastasis in multiple cancer species.…”

“…Among these chemokines, Eisenblaetter et al . recently reported an unusual role of Ccl2 in S100A8/A9‐mediated breast cancer metastasis to the lung . They succeeded in vivo imaging of S100A8/A9 using its antibody‐based SPECT and revealed that Ccl2 mediates tumor metastatic niche formation in the lung before cancer cells migrate to the lung.…”

“…18 Among these chemokines, Eisenblaetter et al recently reported an unusual role of Ccl2 in S100A8/A9-mediated breast cancer metastasis to the lung. 7 They succeeded in vivo imaging of S100A8/A9 using its antibody-based SPECT and revealed that Ccl2 mediates tumor metastatic niche formation in the lung before cancer cells migrate to the lung. Namely, breast cancer located in the mammary fat pad stimulates Ccl2 induction in the remote lung and causes an increase in the CCR2 high CX3CR1 low monocyte population in the same place, where Ccl2 readily binds to its receptor CCR2 in the CCR2 high CX3CR1 low monocytes, resulting in a large amount of S100A8/A9 secretion from the monocytes.…”

Quantitative proteomic profiling of tumor-associated vascular endothelial cells in colorectal cancer

“…A total of 216 DEPs were identified, and then GO analysis and systematic pathway-based enrichment analysis was performed. Among the DEPs, many have been reported or predicted as potential targets for cancer antiangiogenic treatment (see Figure 1D and Supplementary Table S4), such as FBLN5 (Albig & Schiemann, 2004), CEACAM6 (Zang et al , 2015), S100A9 (Eisenblaetter et al , 2017; Zhang et al , 2017), THBS1 (Lawler, 2002), CANX (Demeure et al , 2016), TNC (Kawamura et al , 2018), HSP47 (Wu et al , 2016), CTTN (Ramos-Garcia & Gonzalez-Moles, 2018), MMP9 (Gupta et al , 2013), TGM2 (Lei et al , 2018), S100A7 (Padilla et al , 2017), LCN2 (Hu et al , 2018), RACK1 (Wang et al , 2011), PGK1 (Shichijo et al , 2004), EPO (Samoszuk et al , 1996), CD74 (Gai et al , 2018), GRP78 (Kao et al , 2018). For these candidate antiangiogenic targets, our results are consistent with previously published data.…”