Anticancer Immunotherapy to Circumvent Tumor Resistance to Immune Checkpoint Inhibitors

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Researchers at Johns Hopkins have engineered a new class of cancer immunotherapy agents designed to short-circuit key mechanisms of tumors’ disruption and evasion of immune system attack.
Researchers at Johns Hopkins have engineered a new class of cancer immunotherapy agents designed to short-circuit key mechanisms of tumors’ disruption and evasion of immune system attack.

Despite remarkable outcomes for some patients, most cancers are resistant to ― or acquire resistance to ― to immune checkpoint inhibitors (ICI), therapeutic antibodies designed to target immune-inhibiting programmed death-1 (PD-1)/PD-1 ligand (PD-L1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4) proteins.

Researchers believe that a factor related to a tumors ability to evade ICI  is a versatile cellular signaling protein known as transforming growth factor-β (TGFβ).1-3 This cytokine is involved in a complex web of cellular processes, including proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, invasion, movement, and metastasis.

Most cancers evolve to overexpress TGFβ, probably as natural selection pressure from immune attacks to drive the evolution of immune-evasion mechanisms.

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Tumor-secreted TGFβ inhibits CD8+ killer T cell and type 1 T helper cell (TH1) activity and induces the differentiation of FOXP3-expressing regulatory T cells (Tregs) in the tumor microenvironment, researchers at Johns Hopkins University School of Medicine reported in a recent paper published in Nature Communications.3 These Tregs are a subset of immune cells that inhibit other immune system cells.

“Tregs have long been a thorn in the side of cancer immunotherapy,” said associate professor Atul Bedi, MD, MBA, of Johns Hopkins University School of Medicine in Baltimore, Maryland.

Besides redirecting differentiation of CD4+ T cells away from the TH1 lineage to a Treg phenotype, TGFβ attenuates the activation and cytotoxic function of CD8+ effector cells, and inhibits the development of central memory T cells.

That dysregulation of immune cell activity near the tumor can be a matter of life and death. The cellular ecology of the tumor microenvironment has been linked to patient prognosis.3

“Whereas TH1 cells, cytotoxic CD8+ T cells and central memory T cells are uniformly and strongly associated with a longer disease-free survival, infiltration of tumors with Tregs has been correlated with a poor prognosis in patients with several types of cancer,” Dr Bedi and colleagues explained.

But the researchers reasoned that if the differentiation and function of tumor-infiltrating  Tregs can be blocked, then ICI therapies might more effectively promote immune cell attacks on tumor tissue.

The researchers screened tumors from patients with a range of cancers and found a strong correlation between TGF-β signalling and expression of FOXP3, the signature transcription factor of the Treg lineage that triggers expression of CTLA-4 and other T cell inhibitory ligands.2,3

“As Tregs express and employ TGFβ to maintain their own phenotype and function, enhancing the efficacy of immune checkpoint inhibitors requires a strategy to specifically break this hyperactive autocrine loop in tumor-infiltrating Tregs,” the researchers argued in their Nature Communications paper.3

So they invented  a new investigational class of immunotherapies — “bifunctional antibody-ligand traps” (Y-traps) — to do just that. They engineered Y-traps composed of an antibody targeting either CTLA-4 or PD-L1, joined with a TGFβ receptor II domain (TGFβ RII) via a flexible linker (a-CTLA-4-TGFβRII and a-PD-L1-TGFβRII). These bifunctional therapeutics, which really are Y-shaped, attach to their primary targets (either CTLA-4 or PD-L1) and simultaneously sequester TGFβ, functionally disabling them in the tumor or T cell microenvironment.3  These  Y-traps were designed to short-circuit TGFβ-mediated differentiation of Tregs and immune tolerance in the tumor milieu, and thereby enhance the efficacy of ICI.

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