MIF inhibition as a strategy for overcoming resistance to immune checkpoint blockade therapy in melanoma.

Immune checkpoint blockade (ICB) has demonstrated an impressive outcome in patients with metastatic melanoma, yet, durable complete response; even with Ipilimumab/Nivolumab combo are under 30%. Primary and acquired resistance in response to ICB is commonly due to a tumor immune escape mechanism dictated by the tumor microenvironment (TME). Macrophage Migratory Inhibition Factor (MIF) has emerged as an immunosuppressive factor secreted in the TME.

Melanoma Evolves Complete Immunotherapy Resistance through the Acquisition of a Hypermetabolic Phenotype.

Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them with the same treatment regimen until they developed complete resistance.

Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy.

Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors.

Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway.

Agonist antibodies targeting the T-cell costimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across preclinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist-driven tumor immunity from hepatotoxicity.

Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8 T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8 T cells that express PD-1 and suppress tumor growth.

Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity.

Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment-including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs-can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T-cell checkpoint-modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multifocal disease.