On Feb. 4th, 2021, the Zhang lab from Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences in Peking University, collaborating with Jiafu Ji’s and Zhaode Bu’s teams from Peking University Cancer Hospital, published a resource article entitled “A Pan-Cancer Single-Cell Transcriptional Atlas of Tumor Infiltrating Myeloid Cells” on Cell. The researchers systematically characterized the tumor-infiltrating myeloid cells in 15 cancer types at the single-cell level and compared the characteristics of mast cells, dendritic cells, monocytes, and macrophages in different cancer types, providing valuable insights for the immunotherapy targeting myeloid cells in different tumors.

　　Tumors are complex ecosystems. As myeloid cells constitute a critical cellular component of immune cells that infiltrate into tumors and play essential roles in modulating tumor inflammation and angiogenesis, they have become promising target cells for cancer immunotherapy in pre-clinical and clinical studies. Although single-cell RNA-seq (scRNA-seq) technologies have been widely applied to characterize tumor-infiltrating immune cells and identified several novel myeloid cell populations in specific cancer types, it is not clear whether such findings can be extended to other cancer types. Therefore, by integrating the newly generated scRNA-seq data and the publicly available data, the researchers constructed a pan-cancer landscape of myeloid cells in 15 cancer types and systematically investigated the unique composition and characteristics of those myeloid subsets in different cancer types (Figure 1).

　　Figure 1. The graphical abstract of the pan-cancer analyses

　　The researchers examined the composition of the major lineages of myeloid cells in each tumor type and found that the proportion of mast cells showed dramatic variation across different tumors. For instance, mast cells were largely absent in uterine corpus endometrial carcinoma and hepatocellular carcinoma, whereas the ratio of mast cells was relatively high in nasopharyngeal cancer. Furthermore, the researchers found that the ratio of TNF+/VEGFA+ mast cells in nasopharyngeal cancer was significantly higher than that of other cancer types, suggesting the tumor-infiltrating mast cells in nasopharyngeal cancer exhibited an anti-tumor phenotype. Based on the analyses of cell-cell interactions, they speculated that the IL1B+ macrophages enriched in nasopharyngeal cancer might drive the anti-tumor property of mast cells through the interaction between IL1B-ADRB2.

　　The researchers previously reported that the LAMP3+ cDCs represented a distinct subset of mature cDCs in hepatocellular carcinoma. Here, the researchers demonstrated that the mature dendritic cells (LAMP3+ cDC) were broadly present in diverse tumors, implying their indispensable roles in the tumor microenvironment. The researchers found that the LAMP3+ cDCs from different developmental origins (cDC1 and cDC2) exhibited noticeable transcriptomic differences. Consistent with the previous finding, IL12B, which could induce the differentiation of T helper 1 (TH1) cells, was specific to cDC1-derived LAMP3+ cDCs. cDC1-derived LAMP3+ cDCs also showed higher expression of BTLA, which could induce Treg differentiation and result in immune tolerance. By contrast, cDC2-derived LAMP3+ cDCs still maintained high expression of cDC2 marker gene CD1E and showed higher expression of CCL17, a chemokine that could recruit CCR4+ Treg into the tumor and create the immunosuppressive environment. The researchers further highlighted their differences in transcription factors and external stimulus. These findings imply that, although the two cDC subsets could converge after differentiating into LAMP3+ cDCs, they maintain specific transcriptomic properties, which might diversify their functions.

　　The researchers also compared the transcriptomic similarities of myeloid cell subpopulations and found that macrophages were highly heterogeneous across different tumors, indicating that macrophage subsets exhibited a high level of complexity, which might be related to the dominant effects of the local tissue microenvironment on macrophages. In particular, the researchers found that the pro-angiogenic tumor-associated macrophages (TAMs) were characterized with diverse markers across different cancer types and were typically associated with poor prognosis. The pro-angiogenic SPP1+ TAMs previously reported in colon cancer were identified in 8 tumor types. In tumors with no SPP1+ TAMs found, compensatory tumor-enriched macrophages usually existed with a pro-angiogenic signature, including VCAN+ TAMs in breast cancer and melanoma, INHBA+ TAMs in stomach cancer and esophageal carcinoma, and FN1+ TAMs in kidney cancer. These results indicate that immunotherapy targeting TAMs in different tumors should consider their transcriptional specificity in different cancer types.

　　Sijin Cheng, a postdoc of the School of Life Sciences at Peking University, and Ziyi Li, a Ph.D.  graduate from the School of Life Sciences at Peking University, are the co-first authors. Professor Zemin Zhang from the School of Life Sciences at Peking University, Zhaode Bu, and Jiafu Ji from Peking University Cancer Hospital & Institute are the co-corresponding authors. This project was funded by National Natural Science Foundation of China, the Beijing Advanced Innovation Center for Genomics, and the assistance and support from the high-throughput sequencing platform at Peking University.

　　Link: https://www.cell.com/cell/fulltext/S0092-8674(21)00010-6