How do T cells cross vessel walls to reach tumors?

BUFFALO, N.Y.—Some of the most exciting recent advances in cancer treatment have involved adoptive T cell therapy, in which a patient’s immune cells are retrained to recognize and attack tumor cells. New findings reported by Roswell Park Cancer Institute (RPCI) researchers in the journal Nature Communications help explain why these approaches have been so effective, revealing a critical role for a particular signaling protein and opening up several possible strategies for improving these emerging cancer therapies.

Visualizing blood vessels in real time, the researchers, led by Dr. Sharon Evans, observed that the chemokine receptor CXCR3 must be present on the T cells, or T lymphocytes, in order for these important cancer-fighting cells to be delivered to tumors. The team, which included collaborators from the University of Rochester Medical Center/Wilmot Cancer Center, the University of Chicago and Massachusetts General Hospital/Harvard Medical School, was surprised to find that CXCR3 molecules serve the same function in both human melanoma cells and in preclinical models of melanoma, and that other similar chemokine receptors do not possess this ability.

“We used a special microscope, which made this study unique,” says Evans. “Tumors were implanted on the back of mouse models, like a slide of living tissue. T cells are in the bloodstream but have to cross the vessel wall. Tumor vessels are leaky, but not that leaky.”

These results suggest that the mechanisms governing T cell homing are more complex than previously realized, and that T cells may respond differently to trafficking cues depending on the disease setting. While T cell trafficking across blood vessels has been acknowledged as a key step in immune-driven tumor killing, little was previously known about the directional signals that these white blood cells must receive in order to move out of the bloodstream and pursue cancer cells. “Immune cells can be produced by the billions,” Evans observes, “but how do you get cells into tumors? What kind of molecules support trafficking?”

“Our study is the first to define the molecular cues necessary for delivery of killer T lymphocytes to tumor beds during cancer immunotherapy, and the first to observe that this receptor is a necessary contributor to adoptive cell transfer immunotherapy,” says Evans, the paper’s senior author, who is a professor of oncology in the Department of Immunology at Roswell Park. “While this research focused on melanoma, we believe the findings will be relevant for many other types of cancer, including colorectal, breast and pancreatic cancer.”

Personalized profiling of a patient’s tumor without functional analysis provides only a partial picture of how effective T cell therapeutics are likely to be, according to the researchers.

“The unique role for CXCR3 and its ligands that we uncovered through this work could not have been predicted from genomic or proteomic profiling of the tumor microenvironment,” notes first author Dr. Maryann Mikucki, a trainee in the Department of Immunology at RPCI.

Following on these findings, Roswell Park researchers are looking into the mechanisms that tumors use to block recruitment of killer T cells and ways to address those impediments. Further study will also be needed to better understand why T cells exhibit a preference for CXCR3 over other chemokine receptors during T cell homing to tumor sites and to exploit this CXCR3 requirement in the clinical setting with the goal of improving outcomes in cancer patients.

Killer T cells are “decorated with lots of chemokine receptors,” Evans notes, “but only CXCR3 supports migration across the vessel wall. Why do killer T cells need CXCR3? Possibly due to a sort of division of labor,” she opines.

This work was supported by the National Cancer Institute and the National Institute of Allergy and Infectious Diseases. Additional funds were provided by the Joanna M. Nicolay Foundation, University at Buffalo Mark Diamond Research Fund, Jennifer Linscott Tietgen Family Foundation, Roswell Park Alliance Foundation and James P. Wilmot Foundation.

The study, “Non-redundant requirement for CXCR3 signaling during tumoricidal T-cell trafficking across tumour vascular checkpoints,” is available online at nature.com/ncomms.

The mission of RPCI is to understand, prevent and cure cancer. Founded in 1898, RPCI was one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network (an alliance of the nation’s leading cancer centers), maintains affiliate sites and is a partner in national and international collaborative programs.