Cancer Immunology at the Icahn School of Medicine at Mount Sinai. Courtesy: © 2020 Icahn School of Medicine at Mount Sinai.
Cancer Immunology at the Icahn School of Medicine at Mount Sinai. Photo Courtesy: © 2020 Icahn School of Medicine at Mount Sinai.

Researchers at Mount Sinai, New York City’s largest academic medical system, have discovered a pathway that regulates special immune system cells in lung cancer, suppressing them and allowing tumors to grow.

The researchers also figured out how to interrupt this pathway and ramp up the immune system to prevent tumor formation or growth, offering a potential boost to immunotherapy.

The results from their study were published in the Match 2020 edition of Nature.[1]

As part of their study, the researchers analyzed human and mouse lung cancer lesions, specifically studying the highly specialized immune cells called dendritic cells, which are considered the generals of the immune system.

Dendritic cells give other immune system cells, known as T-cells, identifying information from tumors so the T-cells can recognize and fight cancer.

The authors write that while conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival (OS) in cancer patients, reflecting their ability to prime the responses of CD8+ T cells, they can also be found in tumors that resist checkpoint blockade. [2][3][4]

However, certain genetic material in the tumors may be altered, limiting the function of dendritic cells’ via the newly discovered immune regulatory pathway.

Scientists performed high-tech, single-cell RNA sequencing and high-definition imaging on mouse and human tumors to study the dendritic cells’ activity in lung cancer and adjacent noncancerous lung tissues.

They identified a molecular pathway that dampens dendritic cells’ ability to program T-cells to kill. The study also showed that by reversing this new pathway it is possible to significantly improve tumor responses in animals.

Uncovered a new regulatory approach
Based on their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b), they named the cluster of dendritic cells (DCs)  “mature DCs enriched in immunoregulatory molecules” or mregDCs. [1]

The researchers observed that upregulation of the programmed death-ligand 1 (PD-L1) protein, also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)—a key checkpoint molecule—in mregDCs is induced by the receptor tyrosine kinase AXL.

They further noted that while upregulation of interleukin (IL)-12 depends strictly on interferon-γ and is controlled negatively by IL-4 signaling, blocking IL-4 enhances IL-12 production by tumor-antigen-bearing mregDC1s, expanding the pool of tumor-infiltrating effector T-cells and reduces tumor burden.

Checkpoint blockade
The results of the study will be used to designing a clinical trial, to be conducted in collaboration with Regeneron, that is expected to enhance patients’ response to an immunotherapy called checkpoint blockade, by adding a second therapy that blocks the immune regulatory pathway that decreases dendritic cells’ function in tumors.

Although checkpoint blockade therapies have improved cancer treatment, to date, only 20% of cancer patients respond to these kinds of therapies.

“This study highlights the power of single-cell technologies to identify new therapeutic targets in cancer,” said senior author Miriam Merad, MD, Ph.D., Director of the Precision Immunology Institute and Mount Sinai Professor in Cancer Immunology at the Icahn School of Medicine at Mount Sinai, Co-leader of the Cancer Immunology Program at The Tisch Cancer Institute at Mount Sinai, and Director of the Mount Sinai Human Immune Monitoring Center.

Reference
[1] Maier, B., Leader, A.M., Chen, S.T. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature (2020). https://doi.org/10.1038/s41586-020-2134-y
[2] Sánchez-Paulete AR, Teijeira Á, Quetglas JI, et al. Intratumoral Immunotherapy with XCL1 and sFlt3L Encoded in Recombinant Semliki Forest Virus-Derived Vectors Fosters Dendritic Cell-Mediated T-cell Cross-Priming. Cancer Res. 2018;78(23):6643–6654. doi: 10.1158/0008-5472.CAN-18-0933
[3] Salmon H, Idoyaga J, Rahman A, et al. Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity. 2016;44(4):924–938. doi:10.1016/j.immuni.2016.03.012
[4] Broz ML, Binnewies M, Boldajipour B, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell. 2014;26(5):638–652. doi:10.1016/j.ccell.2014.09.007