Refining immunotherapy: a story of different cell types

Now you see me, now you don’t 

The many cells of our immune system constantly patrol our body to take care of intruders, but sometimes the danger comes from within. This is what happens in cancer. Our body’s own cells revolt and form tumors. One of the tricks these cells and tumors use is hiding from the immune system. 

Immunotherapy is the approach in which we teach our immune system to recognize these sneaky cells and take care of them. Agonistic CD40 therapy is an immunotherapy approach in which we activate the molecule CD40 on dendritic cells – cells that are part of our immune system. This CD40, in turn, tells the dendritic cells to raise a red flag for the immune system: ‘tumor here’. 

Prof. Damya Laoui (VIB Center for Inflammation Research, VUB): “CD40 is an emerging target for cancer immunotherapy and several companies are investigating the use of CD40 agonists as novel treatment options in cancer. However, efficacy data are still limited with only a fraction of the patients showing partial responses to CD40 when used as monotherapy. We ​ investigated the resistance mechanism and propose a new combination therapy that could reduce tumor growth in resistant tumors.” 

Raising the flag 

The cells that usually raise that red flag in tumors for the immune system’s soldiers (CD8⁺T cells) are called type 1 conventional dendritic cells, or cDC1. However, using a mouse model of cancer, the team of Prof. Damya Laoui now shows that another type of dendritic cell, cDC2, can also do this during agonistic CD40 therapy. When the researchers shut down the cDC1 cells, their cDC2 colleagues could pick up the slack and signal the CD8⁺ T cell soldiers to kill the cancer cells. 

That, however, does not explain why some tumors remain resistant to agonistic CD40 therapy. The researchers show that yet another type of immune cell has a role to play here. Tumor-associated macrophages, TAMs for short, are immune cells that linger in the tumor microenvironment. That sounds good, but they are actually bad news. TAMs can cause local inflammation, which can promote cancer growth. This new study finds that TAMs can also suppress the action of the cDCs. The cells can still raise the red flag, but TAMs prevent the T cell soldiers from doing their jobs. ​ 

Moreover, the scientists found a way to make hiding tumors susceptible to the therapy. Some cancer cells remain ‘invisible’ to the dendritic cells. Luckily, chemotherapy can induce cancer cell death, which will release molecules that make the cancer visible again to the dendritic cells. When the researcher depleted the TAMs and treated the tumors with chemotherapy, the subsequent agonistic CD40 therapy was more successful and had longer-lasting effects. ​ 

Aleksandar Murgaski, PhD student in Laoui’s team and first author: “As individuals we are all different from one another, and the way I react to an incident may not be the same as you. We should also think of tumors as individuals, and realize that one single therapy will never be able to have the same effect in every tumor. By understanding the ‘personality’ of individual tumors, we can prescribe combination therapies that steer tumors toward personalities where cancer cells can give the cDCs the flags to raise and TAMs keep the flags up. We believe our work adds to a growing body of research that shows how important it is to understand the traits of individual tumors and fine-tune them for optimal therapeutic effects.” ​ 

This work was done in mice. It represents only the first step toward human application, but it might help to overcome a big hurdle in current forms of immunotherapy and lead the way to a future where all cancer patients receive the optimal therapy for their unique situation. ​ 

Publication

Efficacy of CD40 agonists is mediated by distinct cDC subsets and subverted by suppressive macrophages.

Murgaski et al. Cancer research 2022.

Funding 

This work was funded by FWO, Kom op Tegen Kanker, Stichting tegen kanker, and Vrije Universiteit Brussel. ​