Cancer cell’s “immune escape” still mystifies scientists, even though they have been developing treatments to prevent immune escape and ensure that cancer cells are destroyed by T cells. Scientists hope that by looking behind the curtain, so to speak, they may understand how cancer cells defy cancer immunotherapies such as checkpoint inhibition.
A particularly revealing peak behind cancer’s curtain was reported by scientists based at the University of Freiburgand the Leibniz University Hannover. They observed the early steps that cancer cells take when the follow the programmed death-1 (PD-1) pathway to suppress T-cell stimulation and accomplish immune escape. These steps involve SH2-containing phosphate 2 (SHP2), a tyrosine phosphatase in T cells that has been implicated in T-cell exhaustion.
According to the research team, SHP2 binds to PD-1 in two specific places after it has been activated by a signal from cancer cells. This double binding between SHP2 and PD-1 prevents T cells from recognizing cancer cells, facilitating immune escape.
Details about the double binding appeared in Science Advances, in an article entitled, “Molecular mechanism of SHP2 activation by PD-1 stimulation.” For example, the article describes the SHP2–PD-1 complex structure and explains how it depends on two motifs—immune receptor tyrosine–based inhibitory motif (ITIM) and immune receptor tyrosine–based switch motif (ITSM)—to recruit and activate SHP2, which then removes phosphate groups from nearby effector proteins.
“Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation,” the article’s authors wrote. “We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2.”
According to the authors, this binding event requires the formation of a new interdomain interface, offering opportunities for the development of novel immunotherapeutic approaches.
“Targeting SHP2, as the immediate downstream partner of PD-1, holds promise for the development of a new class of immune modulators,” the article’s authors argued. “Preventing the formation of the interface [between the N-SH2 and C-SH2 domains] would decrease, but not abolish, PD-1 signaling. This strategy could be exploited as part of a combination therapy to reduce cancer immune evasion, while sensitizing cancer cells to other drugs and preventing the side effects caused by full SHP2 inhibition.”
They suggest that their findings could inform the development of small molecule drugs that could disrupt PD-1 signaling in T cells. Such drugs could be less expensive than the monoclonal antibodies that have been used to accomplish checkpoint inhibition.
Checkpoint inhibitors are therapeutic antibodies that work by binding to the receptors of T cells. Proteins on the surface of the T cells called immune checkpoint receptors (such as PD1), along with the signaling pathways that are triggered by them, are what stop immune responses in a healthy body. This regulating mechanism prevents symptoms of inflammation from lasting too long and getting out of control. These symptoms include redness, swelling, and fever.
Cancer cells take advantage of mechanisms such as these to render the body helpless while the cells multiply. Using a combination structural and functional studies in vitro and in cells, the researchers—led by UF’s Prof. Dr. Maja Banks-Köhn and Prof. Dr. Wolfgang Schamel and LUH’s Prof. Dr. Teresa Carlomagno—determined the mechanism of activation of SHP2 by the cytoplasmic tail of PD-1.
Banks-Köhn and Schamel studied the immune response of B cells and T cells by modifying SHP2 molecules, testing the predictions based on crystal structure and magnetic resonance analyses from LUH scientists. Their data shows precisely how and in what areas the SHP2 protein binds to PD1, thereby revealing a possible target area for drugs.
“Drugs that prevent the binding of SHP2 and PD1 could be used in the future to make side-effects less severe and to support, or to act as alternatives to, antibody treatments,” said Banks-Köhn. “In our ongoing research, the next step is to decode the signaling pathway of PD1—in other words, where the proteins are located in the cell, where they bind, and within what time frame the signals take effect.”
M. Marasco, A. Berteotti, J. Weyershaeuser, N. Thorausch, J. Sikorska, J. Krausze, H. J. Brandt, J. Kirkpatrick, P. Rios, W. W. Schamel, M. Köhn, T. Carlomagno. Molecular mechanism of SHP2 activation by PD-1 stimulation. Science Advances, 2020; 6 (5): eaay4458 DOI: 10.1126/sciadv.aay4458Go To Science Advances, 2020