
At a glance:
A protein called STUB1 weakens the cancer-killing power of immune T cells by blocking key signals they need to attack tumors.
Disabling STUB1 in lab experiments strengthened T cells’ response to the immune-boosting molecule IL-27, slowing tumor growth and prolonging mouse survival.
The findings open the door to new approaches that could make cancer immunotherapy work for more patients.
Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this — done in service to humanity — now hangs in the balance due to the government’s decision to terminate large numbers of federally funded grants and contracts across Harvard University.
In a discovery that could expand the array of current cancer immunotherapy treatments, scientists at Harvard Medical School have identified a new molecular brake that hinders the ability of T cells to attack tumors.
The research, published Aug. 12 in Nature Immunology and supported in part by federal funding, offers a new pathway to design treatments that help more patients — a welcome development given that current cancer immunotherapies work in less than half of those who receive them.
The research, done in mice and in human cells, shows that a protein called STUB1 restrains the immune system’s elite cancer-fighting CD8+ T cells. It does so by interfering with immune-signaling receptors — particularly one for the molecule IL-27 — that are crucial for T cells’ ability to mount a vigorous anti-tumor response.
Blocking STUB1, the researchers said, could lead to new ways to supercharge cancer immunotherapies.
“Even though cancer immunotherapies have transformed the way we treat cancer, it’s important that we find new ways to extend the lifesaving and lifechanging benefits of these therapies to more people,” said lead author Martin LaFleur, a postdoctoral researcher in the lab of Arlene Sharpe, the Kolokotrones University Professor in the Blavatnik Institute at HMS, a pioneer in cancer immunotherapy, and senior author on the work. “We believe our work and CRISPR screens more broadly are critical for identifying and prioritizing possible therapeutic targets to find the best ones for patients.”
What the researchers found
Using the gene-editing tool CRISPR, the researchers screened nearly 900 genes to see which ones might be preventing the CD8+ T cells from attacking tumors effectively. One gene stood out: STUB1. When the researchers deleted this gene in CD8+ T cells, these cells became markedly better at attacking tumors. Mice with STUB1-deficient T cells had slower-growing cancers and lived longer than those with unaltered T cells.
Authorship, funding, disclosures
Additional authors included co-lead author Lauren E. Milling, Priyamvada Prathima, Vivian Li, Ashlyn M. Lemmen, Ivy S.L. Streeter, Paul K.S. Heisig, Nicole M. Derosia, Elizabeth Riffo, Haonan Xu, Thao H. Nguyen, Aashiya Kolengaden, Samuel C. Markson, and John G. Doench.
This work was supported by the National Institutes of Health (National Institute of Allergy and Infectious Diseases grant U19AI133524 and National Cancer Institute award 1K99CA290077-01A1), a Cancer Research Institute Immuno-Informatics Postdoctoral Fellowship (CRI5009), and the American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. LaFleur and Sharpe also received funding for this work from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ; the Blavatnik Biomedical Accelerator at Harvard University; the Quadrangle Fund for Advancing and Seeding Translational Research (Q-FASTR) at Harvard Medical School; and Calico Life Sciences LLC.
Sharpe has patents/pending royalties on the PD-1 pathway from Roche and Novartis.
LaFleur, Milling, Streeter, Lemmen, Hesing, Derosia, and Sharpe have a patent on methods for modulating STUB1 for the treatment of cancer. Sharpe is on advisory boards for Elpiscience, Monopteros Therapeutics, Corner Therapeutics, BioEntre, Alixia, GlaxoSmithKline, Janssen, Amgen, AltruBio, ImmVue, and MabQuest. Sharpe receives research funding from Calico Life Sciences LLC and Taiwan Bio. Doench consults for Microsoft Research, Abata Therapeutics, Servier, Maze Therapeutics, BioNTech, Sangamo, and Pfizer. Doench consults for and has equity in Tango Therapeutics. Doench serves as a paid scientific advisor to the Laboratory for Genomics Research, funded in part by GlaxoSmithKline. Doench receives funding support from the Functional Genomics Consortium: AbbVie; Bristol Myers Squibb; Janssen; and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ. Doench’s interests were reviewed and are managed by the Broad Institute in accordance with its conflict-of-interest policies.