BioProject

Solid tumors are composed of cancer cells and host immune cells that are distributed in a non-uniform pattern. More...

Solid tumors are composed of cancer cells and host immune cells that are distributed in a non-uniform pattern. Although this spatial heterogeneity may reflect mutational variations in cancer cells, mechanisms that direct the recruitment of immune cells to distinct regions within a tumor remain poorly understood. Here, we show that microbial-host interactions define tumor nests enriched in immune cells, and the distribution of microbes within tumors parallels the spatial heterogeneity of intratumoral lymphoid and myeloid cell populations. Analysis of human solid tumors revealed that the spatial distribution of immune cells, particularly CD8+ T cells, is markedly heterogeneous. Compared to T cell-poor (“cold”) tumor nests, T cell-rich (“hot”) tumor nests displayed a significantly higher number of myeloid cells, B cells, and plasma cells. We performed laser capture microdissection (LCM) followed by RNA sequencing to identify unique gene signatures that define tumor epithelium and stroma of cold and hot tumor nests. Cold tumor nests expressed genes that promote tumor proliferation and fibrosis, whereas hot tumor stroma and epithelium showed upregulation of immune-related processes, including responses to bacteria, and receptors that mediate mucosal immune responses to microbes, respectively. Consistent with these findings, we detected elevated levels of microbes within hot tumor nests in human pancreatic and lung cancers. Our data implicate host immune responses to microbes in defining intratumoral immune heterogeneity and highlight a potential role for crosstalks between microbes, cancer cells, and the host immune system in regulating cancer immunogenicity. Overall design: RNA isolated from cold and hot tumor nests of human pancreatic ductal adenocarcinoma was analyzed using SMARTer stranded total RNA sequencing. Less...