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A novel immunomodulatory mechanism uncovered in clear cell RCC

BY JIM KLING
MDedge News

Researchers have uncovered a novel immunomodulatory mechanism in clear cell renal cell carcinoma (ccRCC). The discovery centers on the role of an immune complex, called C1, which is made up of components contributed by macrophages and tumor cells. A genetic study suggested that its presence and biochemical activity may be associated with worse prognoses in patients.

The finding could offer a new route to immunotherapy by altering the tumor microenvironment to reduce tumor-enhancing effects, according to Rafael Sanchez-Salas, MD, who is an attendant surgeon at Institute Mutualiste Montsouris in Paris. Dr Sanchez-Salas presented the work at a late-breaking session at the annual meeting of the American Urological Association.

It was long believed that the complement system has primarily an antitumor effect by inducing apoptosis and complement-dependent cytotoxicity.

That’s still true, but recent research has revealed more nuance. The complement system can also be manipulated to lead to immunosuppression and angiogenesis, and to enhance metastasis and proliferation.

At the heart of this activity is the C1 complex, which binds to antibody-antigen complexes and activates the classical complement pathway, which in turn influences the tumor microenvironment in ways that promote tumor growth and spread.

Mice genetically altered to be missing the C1q component of C1 experience slower progression of implanted tumors. Because they lack C1q, C1 cannot be assembled to promote the classical complement pathway, and this may account for their improved survival, compared with wild-type animals.

Clinical research performed by Dr Sanchez-Salas and his colleagues backs that idea. Their analysis of patient samples from The Cancer Genome Atlas found that patients with greater numbers of macrophages producing C1q had worse progression-free survival (P =.00356) and overall survival (P = .00198). When they examined subgroups, they found that higher levels of C1q production were linked to worse outcomes only in patients with advanced disease (progression-free survival, P = .00276; overall survival, P = .0126).

Rafael Sanchez-Salas, MD
The membrane attack complex is one of the methods used by the immune system to attack threats to the body. Compliment dependent cytotoxicity activates the membrane attack complex (MAC) which causes the malignant cell to leak or explode. The C1Q complex consisting of C1Q (blue and green) with serine proteases consisting of dimers of C1r (purple) and C1s (orange) attaches to immunoglobin antibodies which have been attracted by numerous antigens on the surface of the malignant cell. This sequence activates the membrane attack complex which forms pores in the cell membrane.
C1q is primarily produced by M2 macrophages, which naturally infiltrate the tumor microenvironment. But C1 also requires the proteins C1r and C1s. The researchers next examined human ccRCC cell lines and found that the tumor cells produce C1r and C1s. They confirmed that C1q, C1r, and C1s can form active C1 complex in these cell lines, and that it goes on to contribute to formation of the C3 convertase complex C4b2a. This latter complex is a known trigger of the classical complement pathway.
The finding could offer a new route to immunotherapy by altering the tumor microenvironment to reduce tumor-enhancing effects, according to Rafael Sanchez-Salas, MD, who is an attendant surgeon at Institute Mutualiste Montsouris in Paris. Dr Sanchez-Salas presented the work at a late-breaking session at the annual meeting of the American Urological Association.

It was long believed that the complement system has primarily an antitumor effect by inducing apoptosis and complement-dependent cytotoxicity.

That’s still true, but recent research has revealed more nuance. The complement system can also be manipulated to lead to immunosuppression and angiogenesis, and to enhance metastasis and proliferation.

At the heart of this activity is the C1 complex, which binds to antibody-antigen complexes and activates the classical complement pathway, which in turn influences the tumor microenvironment in ways that promote tumor growth and spread.

Mice genetically altered to be missing the C1q component of C1 experience slower progression of implanted tumors. Because they lack C1q, C1 cannot be assembled to promote the classical complement pathway, and this may account for their improved survival, compared with wild-type animals.

Clinical research performed by Dr Sanchez-Salas and his colleagues backs that idea. Their analysis of patient samples from The Cancer Genome Atlas found that patients with greater numbers of macrophages producing C1q had worse progression-free survival (P =.00356) and overall survival (P = .00198). When they examined subgroups, they found that higher levels of C1q production were linked to worse outcomes only in patients with advanced disease (progression-free survival, P = .00276; overall survival, P = .0126).

“This data provides a new mechanism that could be able to modulate the tumor microenvironment of clear cell renal cell carcinoma to improve outcomes,” Dr Sanchez-Salas

However, the strategy would be limited to clear cell renal cell carcinoma, which represents about 70% of kidney cancers. “Each element of the complement activation is expressing very well in renal cell carcinoma, so it’s very unique,” said Dr Sanchez-Salas.

“The next step will be to verify how you can stop this complement activation from happening,” he added, though like any immunotherapy, such inhibition will no doubt have unintended consequences that must be identified and monitored. He expects that any therapy will need to target both macrophage-generated C1q and the tumor-generated C1r and C1s. “If you just target the macrophages [and C1q], you have a problem because endothelial cells can also express C1q. Nature will find a way,” he said.