Reinvigorating exhausted immune cells reveals potential therapy target for cancer

14 Jun 2024
Reinvigorating exhausted immune cells reveals potential therapy target for cancer

The ecosystem that surrounds a tumour, also known as the tumour microenvironment, includes immune cells, tissues, blood vessels and other cells that interact with each other and with the tumour.

Over time, the tumour shapes this ecosystem to its own benefit, monopolising all of the nutrients and shielding it from immune attack. In working to understand the ecosystem’s role in cancer risk, development and treatment, researchers at The Jackson Laboratory have not only identified how two immune cells work together to fight cancer but also revealed the cascade of molecules that help coordinate this attack.

The work, led by JAX Assistant Professor Chih-Hao “Lucas” Chang, Ph.D., focuses on cytotoxic T-cells, a type of immune cell with many functions, including destroying cells infected with viruses and fighting bacterial infections and other pathogens.

They also attack tumour cells. Our immune systems are able to eliminate most cancerous cells from our body before they can cause a problem.

But once a tumour becomes established, cytotoxic T-cells become “exhausted” in the hostile tumour microenvironment and unable to effectively attack tumours. Chang and colleagues are investigating why these immune cells become exhausted, and potential ways to signal them back to targeting tumours.

“T-cells are excellent at identifying and attacking cells that become cancerous, but they can become exhausted in the tumour microenvironment; they can become overworked and overstimulated, while also being starved of glucose and other nutrients by tumour cells. Helping these cells to function better could improve cancer treatment strategies, particularly immunotherapies,” said Chang, whose work appears in Cancer Immunology Research.

Previous studies showed that when cytotoxic T-cells are activated, they release signalling molecules called cytokines. Chang and colleagues focused on one of these cytokines, interleukin-3 (IL-3), discovering that as a tumour grows, cytotoxic T-cells progressively lose the ability to produce IL-3 in the tumour microenvironment.

Then, when Chang elevated IL-3 levels in mice bearing lymphoma or melanoma tumours, he observed strong antitumor effects.

Chang’s team further revealed that IL-3 works to mobilise basophils, a rare immune cell that can also play a role in allergies. In turn, these basophils produce another cytokine known as interleukin-4 (IL-4), which reenergizes cytotoxic T-cells, signalling them to resume detecting and destroying tumours. “Basophils have not previously been implicated in the signalling cascade for reinvigorating cytotoxic T-cells,” said Chang.

“These findings are preliminary, but targeting tumour-associated basophils represents a promising avenue for enhancing antitumor immunity and improving patient outcomes.”

Source: Jackson Laboratory