A new study defines a key subset of T cells in the microenvironment of human lung cancer that physically interact and directly communicate with antigen presenting dendritic cells to protect tumor cells from the body’s anti-tumor immune response. The authors also show how immunotherapy co-opts these cells to kill tumor cells.

Tumors grow in a complex ecosystem of interacting cancer, immune and supporting stromal cells. Understanding the intricacies of this complex crosstalk can be of therapeutic advantage, as seen in immune checkpoint blockade therapies that inhibit T cells that prevent immune cells from attacking the tumor.

A new study published in the journal Nature Cancer on March 3, 2022, takes a closer look at cellular communications within the tumor microenvironment revealing insights that could enhance the efficacy and specificity of immunotherapies to treat cancer.

Miriam Merad, MD, PhD, director of the precision immunology institute at Mount Sinai is a senior author of the study.

“T cells are responsible for killing tumor cells. However, data from our group and others showed that those T cells need to be reactivated locally to eliminate tumor cells,” said Miriam Merad, MD, PhD, director of the precision immunology institute at Mount Sinai and a senior author of the study. “We did this study to understand what cell types in tumors interact with these T cells.”

The article titled “The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response” characterizes the interactions between T cells and antigen-presenting dendritic cells in the tumor microenvironment.

Merad said, “Using a tour de force assay developed by Merav (the first author of the study) we were able to analyze cells that are physically interacting in human tumors and learn about their molecular programs. This has not been done before.”

Merav Cohen, PhD, assistant professor at the department of clinical microbiology and immunology at Tel-Aviv University, Israel, is the lead author of the study.

Using Merav’s novel protocol called PIC-seq that sequences RNA from cells that physically interact, the team found that T cells expressing the markers CD4 (cluster determinant 4), PD-1 (Programmed death-ligand 1) and CXCL13 (C-X-C motif chemokine ligand 13) form a major hub of cellular interaction with antigen-presenting dendritic cells in the tumor microenvironment of human non-small cell lung carcinoma (NSCLC). The authors call this group of tumor-specific, genetically identical (clonal) conserved T cells, T-helper tumor (Tht) cells.

“We show that Tht cells preferentially interact with dendritic cells than effector CD8 positive  T cells within the tumor microenvironment,” the authors note. The authors show, in lung cancer lesions, the interaction between dendritic cells and Tht cells may prevent other immune cells from attacking the tumor.

By reconstituting Tht cells in culture and in a mouse model, the team shows that the Tht program is primed in tumor-draining lymph nodes by dendritic cells that present tumor antigens to other cells of the immune system. They also demonstrate, the Tht program is important for harnessing the antitumor response of the immune checkpoint inhibitor, anti-PD-1. When immune checkpoint blockade was used in the animal model, the researchers show, Tht cells were co-opted to work against the tumor. Tht cells played a role in enabling the recognition and removal of tumor cells by the immune system.

“Now we know what [tumor] cell types T cells interact with. We also know what happens during these interactions and we have a path to intervening to modulate these interactions,” said Merad.  “We are going to now block some of the molecules that are induced during the interactions that limit antitumor activity of T cells.”

These findings may help develop the next generation of T-cell/dendritic cell-based cancer immunotherapies. “Our molecular and functional findings support the modulation of Tht–dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy,” the authors concluded.

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