Our immune system struggles to eliminate tumors effectively. By unraveling its strategies, we can enhance its effects on tumor cells and so improve the clinical prospects of cancer immunotherapy. At the Institut Curie, Inserm and CNRS researchers have for the first time used two-photon microscopy in real-time in vivo studies to show how T cells infiltrate a solid tumor.
These “defenders”, methodically surround enemy positions and “patrol” until they encounter a tumor cell, which they have previously learned to recognize. They eliminate the tumor cell, and then resume their rounds. Fast movements of the T cells signal either the absence of the adversary, or the defeat of the enemy on the battlefield. These findings are published in The Journal of Experimental Medicine.
Institut Curie researchers have just filmed how T cells destroy a tumor. The original images have been assembled into twelve video sequences, through a close collaboration between an expert in two-photon microscopy, Luc Fetler, who is an Inserm researcher in the CNRS/Institut Curie Physical Chemistry Unit(1), and immunologists, notably Alexandre Boissonnas in the Inserm Immunity and Cancer Unit(2) at the Institut Curie.
Our body’s defense against infection or a tumor is based on the involvement of a host of components with general or highly specialized tasks. Cytotoxic T cells fall into the latter category. At their surface they have a membrane receptor complementary to the antigen of the tumor cells that are to be eliminated. Alerted by the presence of this antigen, the T cells are activated, and then identify and bind to infectious or tumor cells, before delivering into them a fatal load of enzymes.
When T cells infiltrate a tumor
Before Alexandre Boissonnas and Luc Fetler did this work, no one had observed on a cellular scale what happens when activated T cells arrive in a solid tumor. Their original experimental model sheds light on the strategy adopted by T cells to destroy the tumor.
Recognition of the tumor antigen determines the behavior of T cells. This conclusion emerged from the researchers’ observation in mice of the movements of T cells, in tumors with an antigen, ovalbumin, and in control antigen-free tumors. Tumor cells, with or without antigen, were inoculated into mice, and eight to ten days later, when the tumors had grown to a volume of 500 to 1000 mm3, the mice were injected with a large number of T cells specific for the antigen OVA.
As expected, only the antigen-bearing tumor was eliminated, after one week. In the meantime, a two-photon microscope (see box) was used to watch what happened in the first 150 micrometers of the tumor. Each shot revealed different cell populations, blood vessels, and collagen fibers, and by stitching together several successive images, it was possible to reconstitute the trajectory of a T cell.
The researchers examined the T cells and tumor cells at two distinct periods of tumor growth. In the antigen-free tumor, the T cells ceaselessly patrolled at high speed (about 10 micrometers per minute), whatever the stage of tumor growth. In the antigen-bearing tumor, on the other hand, T cell behavior varied: when the tumor stopped growing, three to four days after the injection of lymphocytes, the T cells patrolled slowly (4 micrometers per minute), and frequently stopped. Their mean speed plateaued at 4 micrometers per minute. Later, when the tumor regressed, most T cells resumed fast movements.
The trajectories of T cells are confined to the dense zones of living tumor cells, but are more extensive and varied in regions littered with dead tumor cells. The Institut Curie researchers conclude that the presence of the antigen stops the T cells, which are busily recognizing and killing the enemy.
When analyzing their distribution in each tumor, the researchers always found T cells at the periphery, but deep penetration, and hence effective elimination of the tumor, was contingent on the presence of the antigen. These findings were validated with two types of experimental tumors, generated by two lines of cancer cells. It is now up to clinicians to verify whether deep penetration of T cells is a criterion of good prognosis.
To optimize immunotherapy, one of the most promising approaches to cancer treatment, we need a better grasp of how the immune system works. The Institut Curie has for many years participated actively in the development of innovative strategies in this regard. Two clinical trials are presently under way at the Institut Curie, one in patients with choroid melanoma and the other in cervical cancer patients.
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