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Colon Cancer Single-Cell RNA-Seq Study Unveils Mechanisms for Myeloid-Targeted Immunotherapies

NEW YORK – Researchers in the US and China have performed single-cell RNA sequencing (scRNA-seq) analyses on colorectal cancer (CRC) cells from humans and comparable myeloid cells from mice, identifying critical cellular interactions regulating tumor immunity and defining mechanisms underlying myeloid-targeted immunotherapies.

In a study published on Thursday in Cell, the researchers described their analysis of immune and stromal populations from CRC patients, which allowed them to identify specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular crosstalk in the tumor microenvironment (TME). When they defined comparable myeloid populations in mouse tumors, they were also able to characterize their response to myeloid-targeted immunotherapy.

Treatment with an anti-CSF1R therapy preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that expressed pro-angiogenic or tumorigenic genes in the mouse and human cells. Treatment with a CD40 agonist antibody preferentially activated a cDC population, and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells, the researchers found.

"Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing," the authors wrote.

While immunotherapies aimed at repressing tumor-associated macrophages (TAMs) have advanced to the clinic, they've shown minimal efficacy against malignant tumors as monotherapies, the researchers noted. In order to develop more effective myeloid-targeted therapies, what's needed is a comprehensive understanding of myeloid cell heterogeneity in solid tumors and the impact of these therapies on immune cell function and crosstalk within the TME.

With this in mind, the researchers used two scRNA-seq platforms to perform a high-resolution analysis of immune and stromal cell populations in tumor, adjacent normal tissue, and blood from CRC patients, and then constructed a cell-cell interaction network to define key cell populations involved in regulating tumorigenesis and anti-tumor immunity. They identified specific populations of TAMs and dendritic cells as central nodes of cellular interaction.

To understand the consequences of modulating the function of these cells, they also performed scRNA-seq to identify analogous immune cell subsets in preclinical mouse tumor models in the context of anti-CSF1R and anti-CD40 antibody treatment. By analyzing both human and mouse scRNA-seq data, the investigators observed the cells' heterogeneity and function.

In contrast to the relatively stable phenotypes of lymphocyte, stromal, and DC subsets across different tissues and cancer types, they noted that the macrophages' distinct characteristics appeared to be dependent on their tissue or tumor of origin. They identified two distinct TAM populations in CRC, consisting of C1QC+ and SPP1+ TAMs, both of which may arise from an intermediate state of FCN1+ monocyte-like cells in the tumor. C1QC+ TAMs showed preferential expression of genes involved in phagocytosis and antigen presentation, while SPP1+ TAMs were enriched for regulators of angiogenesis. Only SPP1+ TAMs exhibited preferential enrichment in tumor compared to normal mucosa from healthy donors, suggesting their key roles in the tumorigenesis of CRC.

"Depleting immunosuppressive TAMs is an attractive therapeutic approach to promote anti-tumor immune responses. However, their heterogeneity, diverse functions, and predicted cell-cell interaction patterns argues for more subset-specific strategies," the authors wrote.

Indeed, they added, although CSF1R blockade has resulted in significant TAM depletion, CSF1R inhibition as a monotherapy has provided minimal therapeutic benefit in cancer patients as tumors may engage multiple compensatory mechanisms to limit the therapy's anti-tumor activity. The researchers' mouse data combined with their human cancer analyses suggested that specific depletion of SPP1+ TAMs could ultimately lead to improved myeloid-targeted immunotherapy or enhanced combination with ICB therapies.

"Taken together, our study reveals previously unappreciated myeloid-T cell and myeloid-stromal connections within CRC, providing mechanistic insights for immunotherapies currently in clinical development, and demonstrates an approach for dissecting the role of specific tumor-associated immune populations through complementary single cell analysis of both human and mouse tumors," the authors concluded.

They provided their datasets in an interactive portal as a resource for additional exploration of tumor-infiltrating immune cells in humans and mice.