Background: Gene level cell-to-cell communications are crucial part of biology as they may be potential targets of drugs and vaccines against a disease condition of interest. Yet, there are only few studies that propose algorithms on this particularly important research field. Results: In this study, we first overview the current literature and define two general terms for the types of approaches in general for gene level cell-to-cell communications: Gene Regulatory Cross Networks (GRCN) and Gene Co-Expression Cross Networks (GCCN). We then propose two algorithms for each type, named as GRCNone and GCCNone. We applied them to reveal communications among 8 different immune cell types and evaluate their performances mainly via membrane protein database. Also, we show the biological relevance of the predicted cross-networks with pathway enrichment analysis. We then provide an approach that prioritize the targets by ranking them before experimental validations. Conclusions: We establish two main approaches and propose algorithms for genome-wide scale gene level cell-to-cell communications between any two different cell-types. This study aims accelerating this relatively new avenue of research in cross-networks and points out the gap of it with the well-established single cell type gene networks. The proposed algorithms have the potential to reveal gene level interactions between normal and disease cell types. For instance, they might reveal the interaction of genes between tumor and normal cells, which are the potential drug-targets and thus can help finding new cures that might prevent the prevailing of tumor cells.
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