Rerouting dead tumor debris enhances cancer immunotherapy outcomes

As tumors outgrow their blood and nutrient supplies, or respond to treatments like chemotherapy and radiotherapy, individual cancer cells die, exposing their internal scaffolds. These dead cells are an abundant source of mutated proteins, or antigens, that can mark cancer cells as different from healthy ones. This is exactly what the immune system needs to recognise a tumor.

But a persistent puzzle in immunology is that many cancers remain poorly recognised by the immune system despite carrying large numbers of potentially visible antigens.

As Caetano Reis e Sousa, head of the Immunobiology Laboratory at the Crick, explains, "This reveals a blind spot in cancer immunity, where antigen presence alone is not enough to trigger an effective response."

Caetano's team have previously shown how specialized immune cells called dendritic cells can detect cancer cells after components of their internal scaffold become exposed. But only a very small proportion of immune cells have this ability - type 1 conventional dendritic cells (cDC1s) are particularly effective at capturing material from dead cancer cells and presenting it to T cells.

Overcoming the blind spot

In their latest study, published in Nature Cancer, the team have leveraged this understanding to promote anti-cancer immunity by redirecting other, more abundant immune cells to take on the same role.

Tom Castro Dopico, a Postdoctoral Fellow in the lab, developed biological reagents that link F‑actin from the scaffolding of dead cancer cells to receptors on nearby immune cells, effectively rerouting how this material is handled and triggering a T‑cell response against the tumor.

"When we tested this approach in mice, these antibodies effectively redirected non‑specialised immune cells to present a broader range of tumor antigens, leading to reduced tumor growth," he describes. "This effect was strongest when combined with chemotherapy or radiotherapy, which increase the amount of dead tumor material, and therefore exposed F‑actin."

Implications for immunotherapy

For Caetano, addressing this blind spot opens new avenues for developing immunotherapy treatments that complement existing clinical approaches. "We're interested in how therapies might be refined by paying closer attention to what dying cells leave behind," he adds. "Treatments such as chemotherapy and radiotherapy already create large amounts of tumor debris. By training the immune system to handle this material differently, we hope to amplify responses to tumors that would otherwise remain hidden."

In 2021, Caetano co-founded Adendra Therapeutics to explore this opportunity further. Armed with this fresh insight into dendritic cell biology and a route to reshaping how the immune system sees cancer, the challenge is now to further refine anti F-actin reagents such as antibodies for safe use in people, and test whether they can trigger a consistent and lasting response in patients.

These results are exciting because they confirm that much of what is currently ignored by the immune system in cancer can be redirected to enhance anti-tumor immunity."

Raj Mehta, co-founder and CEO, Adendra Therapeutics

Broadening of immune to tumor antigens has been shown to be required for efficacy of most immunotherapy approaches for treatment of cancer. Cross training non-cDC1 cells to enhance epitope spreading presents an opportunity to develop highly targeted immunotherapy treatments as single agents or in combination with other immune mediated therapies.