In a breakthrough that could broaden the scope of existing cancer immunotherapy treatments, scientists at Harvard Medical School have discovered a novel molecular brake impeding T cells' ability to combat tumors.
The study, published in Nature Immunology, uncovers a new avenue for developing therapies that can benefit more patients—a significant advancement considering current cancer immunotherapies are effective in less than half of treated individuals.
Nature ImmunologyThe research, conducted on mice and human cells, reveals that a protein named STUB1 restricts the immune system's powerful CD8+ T cells by interfering with key immune-signaling receptors—including those for IL-27—that are essential for mounting an effective anti-tumor response.
Inhibiting STUB1 could pave the way to enhance cancer immunotherapies significantly.
"Although cancer immunotherapies have revolutionized cancer treatment, extending their lifesaving benefits to more people is crucial," said lead author Martin LaFleur, a postdoctoral researcher in Arlene Sharpe's lab at HMS. Sharpe, the Kolokotrones University Professor in the Blavatnik Institute and a pioneer in cancer immunotherapy, is also a senior author on this study.
"Our work, along with CRISPR screens generally, is vital for identifying and prioritizing therapeutic targets to benefit patients most effectively."
Utilizing the gene-editing tool CRISPR, researchers screened nearly 900 genes to determine which might prevent CD8+ T cells from effectively attacking tumors. STUB1 emerged as a key candidate. When this gene was deleted in CD8+ T cells, these cells displayed enhanced tumor-fighting capabilities. Mice with STUB1-deficient T cells exhibited slower cancer growth and lived longer compared to those with unaltered T cells.
STUB1The experiments demonstrated that STUB1 diminishes the ability of T cells to detect and respond to immune-boosting cytokines by interacting with another protein, CHIC2. This interaction removes key cytokine receptors from T cell surfaces, making these immune defenders less responsive to activating signals from cytokines.
Blocking the interplay between STUB1-CHIC2 could amplify the body's natural defenses against cancer, suggesting new treatment possibilities.
While primarily conducted on mice, the research indicates similar processes may occur in humans. Additional experiments with human T cells showed that removing STUB1 or CHIC2 led to elevated levels of cytokine receptors, mirroring findings in mice.
Furthermore, a recent study linked IL-27 signaling with improved killer T-cell and immunotherapy responses in human patients, suggesting that inhibiting STUB1 may enhance tumor immunity through similar pathways.
The discovery could lead to new drug therapies or cell-based approaches. For instance, engineering T cells lacking STUB1 may prove effective, especially since STUB1 is widely expressed and selective removal from T cells can boost their function while minimizing potential systemic toxicities.
Additionally, these findings address two critical gaps in cancer immunotherapy:
First, scientists lack full understanding of the signals that prompt T cells to mount a robust anti-tumor response. This study shows STUB1 suppresses cytokine signaling during early T-cell responses and identifies IL-27 as an important priming signal for T cells.
Second, blocking STUB1 presents an intriguing therapeutic approach, as it enhances both T cells' anti-tumor responses and vulnerability of tumors to immune attack.
"STUB1 inhibition could be valuable either as a standalone therapy or in combination with existing treatments," LaFleur noted. "Since STUB1 influences early T-cell priming, it could enhance therapies targeting later stages of the T-cell response."
The researchers underscore the need for further studies to comprehensively understand the promise, safety, and efficacy of STUB1 inhibition in humans. Nevertheless, these findings provide critical insights into how the immune system battles cancer and suggest methods for improving its effectiveness.