Abstract: Histopathological imaging is vital for cancer research and clinical practice, with multiplexed Immunofluorescence (MxIF) and Hematoxylin and Eosin (H&E) providing complementary insights. However, aligning different stains at the cell level remains a challenge due to modality differences. In this paper, we present a novel framework for multimodal image alignment using cell segmentation outcomes. By treating cells as point sets, we apply Coherent Point Drift (CPD) for initial alignment and refine it with Graph Matching (GM). Evaluated on ovarian cancer tissue microarrays (TMAs), our method achieves high alignment accuracy, enabling integration of cell-level features across modalities and generating virtual H&E images from MxIF data for enhanced clinical interpretation. Keywords: Histopathology alignment, Histopathology registration, Bioimage analysis Introduction: As an important approach to reveal cell level details in cancer, histopathological images have been widely used in both clinic practice for diagnostic decision making and treatment follow up. Following different staining protocols, each modality of histopathology has its unique strength in highlighting specific aspects within tumor immune microenvironment (TIME). Among which, multiplexed Immunofluorescence (MxIF) images provide refined immune cell phenotyping, making it a favorable research tool for revealing cell behaviors in TIME. However, this imaging technique now is mainly used for research purposes due to the low reliability of marker signals caused by complex cyclic staining processes. On the other hand, H&E (Hematoxylin and Eosin) staining plays an irreplaceable role in providing standard clinical references by revealing cell morphology and texture patterns.

Understanding the way cells communicate, co-locate, and interrelate is essential to furthering our understanding of how the body functions. H&E is widely available, however, cell subtyping often requires expert knowledge and the use of specialized stains. To reduce the annotation burden, AI has been proposed for the classification of cells on H&E. For example, the recent Colon Nucleus Identification and Classification (CoNIC) Challenge focused on labeling 6 cell types on H&E of the colon. However, the CoNIC Challenge was unable to classify epithelial subtypes (progenitor, enteroendocrine, goblet), lymphocyte subtypes (B, helper T, cytotoxic T), and connective subtypes (fibroblasts). We use inter-modality learning to label previously un-labelable cell types on H&E. We take advantage of multiplexed immunofluorescence (MxIF) histology to label 14 cell subclasses. We performed style transfer on the same MxIF tissues to synthesize realistic virtual H&E which we paired with the MxIF-derived cell subclassification labels. We evaluated the efficacy of using a supervised learning scheme where the input was realistic-quality virtual H&E and the labels were MxIF-derived cell subclasses. We assessed our model on private virtual H&E and public real H&E. On virtual H&E, we were able to classify helper T cells and epithelial progenitors with positive predictive values of $0.34 \pm 0.15$ (prevalence $0.03 \pm 0.01$) and $0.47 \pm 0.1$ (prevalence $0.07 \pm 0.02$) respectively, when using ground truth centroid information. On real H&E we could classify helper T cells and epithelial progenitors with upper bound positive predictive values of $0.43 \pm 0.03$ (parent class prevalence 0.21) and $0.94 \pm 0.02$ (parent class prevalence 0.49) when using ground truth centroid information. This is the first work to provide cell type classification for helper T and epithelial progenitor nuclei on H&E.