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Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

Simonds EF, Lu ED, Badillo O, et al. JITC (2021)
Mass cytometry identifies immune population changes in the tumor draining lymph nodes of mice treated with systemic FLT3L monotherapy
Mass cytometry identifies immune population changes in the tumor draining lymph nodes of mice treated with systemic FLT3L monotherapy

The team Simonds, Lu, & Badillo et al. sought to determine why glioblastoma, the most common malignant brain tumor, is also the most resistant to immunotherapy. Using mass cytometry, the team compared the immune cell populations in two immune checkpoint refractory tumor types, glioblastoma and sarcoma, to renal cell carcinoma (immune checkpoint inhibitor-responsive). Deep immune profiling identified new potential targets among DC and tumor associated macrophage populations.

Single cell profiling of 19 glioblastoma, 11 renal cell carcinoma, and 4 sarcoma tumors was performed using mass cytometry. The team discovered that immunotherapy refractory glioblastoma tumors had very few T cells and a high frequency of myeloid cells while immunotherapy sensitive renal cell carcinoma tumors showed the opposite pattern. Evidence from the team’s mass cytometry profiling points to regulatory T cells as a key player in this system. They observed that FLT3L monotherapy caused expansion of DC and Tregs in tumor draining lymph nodes. The team showed that treatment of intracerebral immune checkpoint-refractory tumors in mice, with a recombinant FLT3-ligand, expanded DCs, boosted tumor-specific CD4 T cell priming, and prolonged survival.

Their data suggests that accurate tumor models and deep immune profiling can be leveraged to further explain the immunosuppressive mechanisms that are unique to brain tumors. These new insights provide resolution on how to better approach, treat and cure, therapy-refractory cancers.

Reference citation: Simonds EF, Lu ED, Badillo O, et al. Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma. Journal for ImmunoTherapy of Cancer 2021;9:e002181. doi: 10.1136/jitc-2020-002181

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Illustration. In the center is a grey mass labeled "tumor" under a magnifying glass. Inside the tumor are three grey cells all with "zzz" above them. Outside the magnifying glass (and therefore outside the tumor) in the four corners are different depictions. Top left shows three red cells and is labeled "novel T cell clones". Top right shows a lymph node with red T cell zones and the words "LN trafficking required". Bottom right shows two red T cells in a blood vessel labeled "LAG-3 and CD8+" with the words "peripheral biomarkers". Bottom left shows a spleen with the same grey, sleeping T cells. There's a red lightning bolt and the words "impaired systemic immune response in cancer".

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Although most research focuses on tumor-killing immune cells at the site of the tumor, new research increasingly demonstrates the value of studying circulating immune cells in peripheral blood to identify new therapeutic targets to enhance tumor-killing immune responses. We highlight recent publications with peripheral blood biomarkers and discuss recommendations for how to incorporate peripheral blood immune profiling into your drug development pipeline.