Able to obtain millions of data point from individual cells, single-cell analysis achieves unprecedented scale and resolution, heard attendees at a joint symposium run by the American Association for Cancer Research (AACR) and the Chinese Society of Clinical Oncology (CSCO) this week: Changing the Landscape of Cancer Research.
Speakers participating in that AACR 2021 event said such technologies are transforming the understanding of cancer biology, allowing researchers to resolve cell-to-cell variation, define novel cell types and cell states, and identify rare cells driving disease progression.
It is important to consider differences in immune cell populations when developing therapies though, said Zemin Zhang, PhD, Biomedical Pioneering Innovation Center, Peking University. “The tumor microenvironment (TME) is the battlefield for immunotherapy. Single-cell sequencing is needed to understand the composition of the TME, the lineages, dynamics, interactions, and clinical relevance of different cell types.”
Zhang and the other speakers discussed innovative approaches to leveraging genome-wide, single-cell resolution data to elucidate diverse aspects of cancer biology, ranging from the identification of cell of origin, to the characterization of infiltrating immune cells, and to the definition of gene programs at the root of malignant disease.
Variability in tumor response to different treatments
There are many T cell-based immune types, Zhang said, all with different sensitivity and resistance to different therapeutic approaches. Immune cell sets and subsets vary widely across cancer types, which might account for the variability in tumor response to different treatments, he reported.
Single-cell RNA sequencing has revealed distinctive subsets of T cells in liver and other cancers, said Zhang. One subset shows clonal enrichment for infiltrating regulatory T cells with fewer exhausted CD8 T cells, the other subset shows fewer infiltrating Tregs and more exhausted CD8+ T cells. “The relative ratios of these two T-cell types varies across different cancers with different clinical implications.”
Cancer-specific myeloid cells also separate into two groups, dendritic cells, and macrophages. In hepatocellular carcinoma, LAMP3+ dendritic cells are usually found inside the tumor but can migrate to lymph nodes and activate other T cells.
Colon cancer contains five subsets of macrophages, Zhang said, including two tumor-associated macrophages, or TAMs. The two TAM subtypes have different properties. CD1C macrophages favor tumor progression, while SPP1 macrophages favor tumor regression, he added.
However, he noted that CSF1R antibody treatment selectively depletes the SPP1 subtype. “You are essentially getting rid of the good guys and keeping the bad guys with CSF1R. This explains why the therapy has been ineffective.”