‘Highjack’ Autoimmunity to Enhance Efficacy of Immunotherapy?

Induced IKZF1 overexpression facilitates tumor infiltration by immune cells and enhances the efficacy of programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint inhibition in skin cancer and other solid cancer types, preclinical research published in Cell Systems suggests. IKZF1 mutations in skin cancer are also associated with poor patient prognosis, the investigators found.

“This work provides proof of concept that tumors can be rendered susceptible by ‘hijacking’ immune cell recruitment signals through molecular master regulators,” reported senior study author Angela M. Christiano, PhD, of the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, in New York.

Cancer immunotherapies are designed to improve antitumor immune response, but tumors have more than one molecular mechanism of immune evasion. As a result, most patients do not benefit from immune checkpoint inhibition.

“One avenue for enhancing treatment for these patients is by converting these tumors to an immunoreactive state, thereby restoring treatment efficacy,” the study authors wrote. “[W]e propose a strategy for enhancing cancer immunotherapy that entails ‘hijacking’ the molecular mechanisms that activate the immune system in autoimmune disease and using them to essentially ‘tag’ evasive tumors for immune-mediated destruction. We reasoned that the molecular processes that encourage active immune cell infiltration to the target organs in autoimmune disease could be used to restore immune targeting against cancer cells.”

IKZF1 is one key regulator of autoimmunity-associated cytotoxicity. IKZF1 has been implicated in immune response to invasive skin cancer and, in the presence of other deletion mutations, IKZF1 deletion mutation has been linked to poorer prognosis in B-cell acute lymphoblastic leukemia.

“We hypothesized that tumor cohorts may achieve immune evasion via IKZF1-inactivating mutations,” the study authors explained. “These tumors would then be susceptible to enhancement therapy through the restored expression of IKZF1.”

Using computational DIGGIT (Driver-gene Inference by Genetical-Genomics and Information Theory) analyses of molecular network data on 15 different tumor types from The Cancer Genome Atlas (TCGA), the authors identified cohorts of patients in whom IKZF1 expression is disrupted. They found eight TCGA cancers with targetable disruptions of IKZF1 expression: skin cancer, glioblastoma, head-and-neck squamous carcinoma, lung adenocarcinoma, lung sarcoma, thyroid carcinoma, bladder carcinoma, and prostate adenocarcinoma.

They then introduced IKZF1 into seven human cancer cell lines (skin cancer, glioblastoma, thyroid cancer, prostate cancer, bladder cancer, and lung adenocarcinoma) for testing with immune-mediated cytotoxicity assays. Five IKZF1-transfected cell lines exhibited significant increases in immune-mediated cytotoxicity compared with control cells: two skin cancer cell lines, glioblastoma, thyroid cancer, and prostate carcinoma.

IKZF1 expression also slowed skin cancer graft growth in mice. Subsequent RNA-sequencing–based tumor gene expression analysis showed that increased tumor IKZF1 expression was associated with CD8+ T-cell and other immune cell infiltration in the grafted tumors. When the mouse experiments were repeated with PD-1 and CTLA-4 monotherapeutic and combinatorial immune checkpoint inhibition, IKZF1 expression enhanced immunotherapeutic suppression of skin tumor graft growth. Subsequent mouse experiments validated the skin cancer findings with kidney, prostate, and colorectal cancer tumor grafts.

The authors also found that IKZF1 overexpression modulated immune biomarker expression in human solid tumors, and that mutations affecting IKZF1 expression are associated with fewer immune cell infiltrates in human tumors.

Low IKZF1 expression “predicts recurrence and poor prognosis” in skin cancer, they concluded.