Genentech-led team uncovers how cancer cells resist T-cell attack in potential boon to immunotherapy

Cancer cells deploy various tactics to avoid being targeted and killed by the immune system. A research team led by Roche’s Genentech has now identified one such method that cancer cells use to resist T-cell assault by repairing damage.

To destroy their targets, cancer-killing T cells known as cytotoxic T lymphocytes (CTLs) secrete the toxin perforin to form little pores in the target cells’ surface. Another type of toxin called granzymes are delivered directly into the cells through those portals to induce cell death.

By using high-res imaging in live cells, the Genentech-led team found that the membrane damage caused by perforin could trigger a repair response. The tumor cells could recruit endosomal sorting complexes required for transport (ESCRT) proteins to remove the lesions, thereby preventing granzymes from entering, the team showed in a new study published in Science.

“[The finding] really speaks to the general issue that cancer cells are likely to have multiple ways of avoiding killing, one or all of which may contribute to inherent insensitivity to therapy,” Ira Mellman, Ph.D., Genentech’s vice president of cancer immunology, said in an email to Fierce Biotech Research.

Mellman and Genentech postdoctoral fellow Alex Ritter, Ph.D., are co-corresponding authors of the new study. Others from Howard Hughes Medical Institute and Australia’s Peter MacCallum Cancer Centre also participated.

ESCRT proteins are known as repairers of small wounds and pores in the membrane caused by other sources such as bacterial toxins and mechanical wounding.

In live-cell imaging, the team showed that cancer cells’ recruitment of ESCRT protein matched injury by T cells in terms of both the timing and location. Upon assault by killer T cells, the ESCRT proteins accurately accumulated at cytolytic synapses, sites where T cells bind target cells and initiate the killing process.

To further validate the finding, the researchers inhibited ESCRT by using CRISPR to remove a gene coding for an ESCRT protein or dialing up the expression of a genetic piece that impairs ESCRT function. Compared with control cells, cancer cells with ESCRT inhibited were more efficiently killed off by T cells, the team reported.

The research offers new insights into how tumor cells escape being targeted by the immune system and could be helpful in improving the efficacy of cancer immunotherapies such as PD-1/L1 checkpoint inhibitors and CAR-T cell therapies, which rely on immune cells to go after cancer.

Genentech is currently exploring the combination of its anti-TIGIT antibody tiragolumab with PD-L1 inhibitor Tecentriq and has shown promising midstage clinical results in non-small cell lung cancer. TIGIT is a receptor overexpressed on some T cells that can dampen their cancer-killing activity.

On the ever-growing list of proposals to enhance immuno-oncology agents, researchers at MD Anderson Cancer Center recently showed that antihistamines, by targeting histamine receptor H1, could reverse immune suppression and buoy responses to checkpoint inhibitors. A team from the Karolinska Institute and U.S biotech Aileron Therapeutics previously found that blocking the MDM2 protein could reactivate the p53 protein, known as the “guardian of the genome,” thereby boosting various aspects of an antitumor immune response.

Although ESCRT inhibition represents a promising strategy to enhance T cells’ attack on tumor cells, it isn’t immediately clear how to achieve that with a drug, Mellman noted, because ESCRT proteins are also essential for cell division.

“But I would predict that the complexity of the system, in this case, will yield a ‘way in’ to the problem,” Mellman said. He suspected that some members of the family may be needed for membrane repair but not for other functions.

“Certainly, the ESCRT inhibition experiments, at least in cell culture, produce pretty dramatic increases in sensitivity to CTL attach. So, we will be evaluating this pathway further,” Mellman said.

In an accompanying commentary, University of Maryland cell biologist Norma Andrews, Ph.D., suggests that future studies also explore the roles of other cellular processes in repairing membrane wounds. “This is important because a comprehensive understanding of the plasma membrane resealing mechanism may reveal steps amenable to therapeutic intervention.”