Yang Cui ¹ Weihang ZHANG ¹ Xin Zeng ¹ Yitao Yang ¹ Sung-Joon Park ² Kenta Nakai ^1,2*

• ¹ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
• ² Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan

The tumor microenvironment (TME) plays a crucial role in tumor progression and immunoregulation. Major histocompatibility complex class II (MHC-II) is essential for immune surveillance within the TME. While MHC-II genes are typically expressed by professional antigenpresenting cells, they are also expressed in tumor cells, potentially facilitating anti-tumor immune responses. To understand the role of MHC-II-expressing tumor cells, we analyzed triple-negative breast cancer (TNBC), an aggressive subtype with poor prognosis and limited treatment options, using public bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomics datasets. Our analysis revealed a distinct tumor subpopulation that upregulates MHC-II genes and actively interacts with immune cells. We implicated that this subpopulation is preferentially present in proximity to regions in immune infiltration of TNBC patient cohorts with a better prognosis, suggesting the functional importance of MHC-II-expressing tumor cells in modulating the immune landscape and influencing patient survival outcomes. Remarkably, we identified a prognostic signature comprising 40 significant genes in the MHC-II-expressing tumors in which machine leaning models with the signature successfully predicted patient survival outcomes and the degree of immune infiltration. This study advances our understanding of the immunological basis of cancer progression and suggests promising new directions for therapeutic strategies.