At a glance
A new study has found that some tumors that evade the immune system do so by failing to display cancer signals that T cells can recognize.
Experiments focused on p53, a protein frequently mutated in cancer, revealed several ways that tumors evade immune cells — and showed that one of those mechanisms could be reversed in cells.
The findings suggest that manipulating the protein fragments that cancer cells display may be a useful therapeutic strategy to resensitize tumors to immunotherapies.
One of the biggest challenges in cancer immunotherapy — a treatment approach that helps the immune system recognize and attack cancer — may not be that immune cells are too weak, but that some tumors give them too little to see.
New research from a collaborative team led by HMS scientists at Dana-Farber Cancer Institute reveals how cancers carrying mutations in the tumor-suppressor protein p53 can hide those mutations from cancer-fighting T cells. The work also suggests a countermeasure: Change what the cancer cells display on their surfaces so that the immune system can recognize the tumor.
The study, published Sept. 17 in Immunity, analyzed cells in the lab to identify mechanisms through which tumors can hide p53 mutations and showed that at least one of those mechanisms can be reversed.
“The conventional question has been: How do we make the immune system attack harder?” said co-senior author Ellis Reinherz, HMS professor of medicine at Dana-Farber. “Our results point to a complementary question: How do we make the tumor reveal more?”
How tumors hide
Pancreatic cancer, prostate cancer, ovarian cancer, many breast cancers, and glioblastoma are among the major tumor types commonly described as “cold,” meaning that they sometimes contain few T cells or actively exclude and suppress them. Such tumors can be more difficult to treat with immunotherapies known as immune checkpoint inhibitors than highly inflamed or “hot” tumors, such as many melanomas.
When checking for cancerous cells, T cells do not read a tumor’s DNA directly. Instead, they inspect tiny protein fragments, called peptides, held on the cell surface by molecules known as HLA. If a cancer-specific fragment never appears there, or disappears too quickly, even a highly capable T cell may have nothing durable to attack.
That problem is especially important for p53. Mutations in TP53, the gene encoding p53, occur in roughly half of all human cancers. Because many TP53 mutations arise early in tumor development, they can be passed on to every cancer cell as the tumor grows. Such mutations are therefore attractive immunotherapy targets.
The current study shows why targeting those mutations can be difficult.
The researchers first used an ultrasensitive mass-spectrometry platform to measure which fragments of normal p53 cells actually displayed on their surfaces. Of 175 p53 peptide candidates predicted by computer models to bind to relevant HLA molecules, only five were detectably displayed by cells.
The researchers then examined common cancer-causing p53 mutations. They found that many occurred in regions that tumor cells processed poorly, so the cells failed to generate any fragments on the surface for T cells to recognize.
Furthermore, some tumor samples carrying potentially powerful p53 targets lacked the HLA molecule needed to display them.
In the case of the p53 I195F mutation, high activity of an enzyme called ERAP1 acted like an overzealous molecular trimming machine, destroying an otherwise strongly immunogenic p53 fragment before it could be displayed to T cells. Deleting ERAP1, or blocking it with an inhibitor, restored recognition of those cancer cells by p53-specific T cells in laboratory experiments.
“A tumor may carry an ideal mutation in every cancer cell, but if that mutation is not processed into a stable surface target, making a stronger T cell may not be enough,” added co-senior author David Barbie, HMS professor of medicine at Dana-Farber.
A shift in strategy
Most cancer immunotherapies focus on empowering immune cells. Immune checkpoint inhibitors release molecular brakes on T cells; engineered TCR-T and CAR-T therapies supply large numbers of highly active immune cells.
The new study suggests that, for solid tumors, the other side of the equation may be equally important. The authors call this approach an “immunopeptidome shift.”
Rather than relying only on the peptides that a tumor naturally chooses to display, drugs could make cancer cells reveal new peptide targets. The study points to several possible routes, including ERAP1 inhibitors, small molecules that bind to and change which peptides can fit into HLA molecules, and drugs that alter RNA splicing.
While p53 provides an important test case, the underlying principle is to change what any tumor displays on its surface, regardless of which mutation created the cancer, the authors said.
Displaying more targets could also make immune escape harder, since therapies directed against a single target can fail if cancer cells stop displaying that target. The approach might, therefore, be combined with checkpoint inhibitors, therapeutic vaccines, or engineered T-cell therapies, rather than replacing them, the authors said.
Adapted from a Dana-Farber news release.
Authorship, funding, disclosures
Koji Haratani is the first author of this study. Additional authors on the paper include Bruce Reinhold, Jonathan S. Duke-Cohan, Caroline G. Fahey, Kemin Tan, Robert J. Mallis, Alexander Gusev, Kenneth L. Kehl, Jia Luo, Allyson Karmazyn, Elizabeth L. Holliday, Daniel J. Masi, Katarzyna J. Zienkiewicz, Connor J. Hennessey, Rafael B. Blasco, Tran C. Thai, Grace M. Gibbons, Sophie Kivlehan, Patrick Lizotte, Cloud P. Paweletz, Andrew J. Aguirre, Keith L. Ligon, Roberto Chiarle, and Matthew J. Lang.
This research was supported by the National Institutes of Health (grants R01CA190294, R01CA265928, T32 DK101003, PO1AI143565, P50CA265826, and S10OD030394); Department of Energy (contract DE-SC0012704); Ludwig Center at Harvard; Mark Foundation; Heerwagen, Candice Bagby, and Ming and Polly Tsai Funds for Lung Cancer Research; Takeda Science Foundation; Osaka Medical Research Foundation for Intractable Diseases; Mochida Memorial Foundation for Medical and Pharmaceutical Research; and Nakatomi Foundation.
A full list of disclosures can be found in the paper.
