Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma

Abstract

Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory large B cell lymphoma (LBCL). Here, we evaluated whether immune dysregulation, present prior to CAR-T cell therapy, associated with treatment failure. Tumor expression of interferon (IFN) signaling, high blood levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and high blood IL-6 and ferritin each associated with a lack of durable response. Similar to other cancers, we found that in LBCL tumor IFN signaling is associated with the expression of multiple checkpoint ligands including PD-L1, and these were higher in patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, patients with high tumor burden had higher immune dysregulation with increased serum inflammatory markers and tumor IFN signaling. These data support that immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic programs: insufficient axi-cel expansion associated with both circulating M-MDSC and tumor IFN signaling, that also gives rise to expression of immune checkpoint ligands.

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

“…The differential expression analysis (16 patients with also WGS data available) showed a higher expression level of genes known to be target of tumor signaling in patients treated with CAR-19 (Figure 4c). Interestingly, the ISG.RS signature, previously described to be associated with Tcell exhaustion and worse outcome after immunotherapy 12,48 , was enriched in r/r patients harboring at least one reported genomic driver (Figure 4d), while the INFG.GS signature, associated with higher response to check point blockade, was enriched in patients without any significant genomic drivers (Supplementary Figure 6). Moreover, the cases containing at least one reported genomic driver were characterized by higher MTV, reflecting the relationship between disease aggressiveness and the TME (Figure 4e).…”

“…In this scenario, the CAR-T cells act as a gateway into the immunosuppressed TME to allow the host immune system to destroy the tumor. Data from axi-cel-treated patients showed that patients with high serum inflammatory markers, along with increased tumor IFN signaling were indicative of lack of durable response 12 . Recent studies by Alizadeh et al 53 demonstrated that CAR-T cells secrete IFN gamma and activate host T cells in a mouse model of glioblastoma and these cells preserved their anti-tumor activity also when infused without CAR-T.…”

“…It has been shown that distinct tumor immune microenvironmental patterns correlate with clinical outcome in patients treated with CAR-19 12,13 . In this study, we showed how distinct and complex genomic features in the tumor cells are strongly predictive of outcome in the same setting.…”

“…Disease aggressiveness and serum inflammatory markers associate with poor outcome 5,10,11 , as does T-cell exhaustion in either the tumor microenvironment (TME) 12 or the CAR-19 product 13 .…”

Combined Effects of Myeloid Cells in the Neuroblastoma Tumor Microenvironment

“…With their heterogeneous range of suppressive mechanisms, myeloid cells have become a major target to consider for combinatorial approaches with CAR T cells, checkpoint inhibitors, and NK cell-based therapies. Indeed, it has been demonstrated that not only do myeloid phenotypes positively correlate with CAR T therapy failure [159], but also that ablation of these populations can improve antitumor effects of various immunotherapeutics [160][161][162][163]. Strategies to overcome myeloid-mediated suppression of the immune response can be generally categorized into (1) prevention of recruitment to the tumor, (2) depletion of myeloid populations or disruption of their suppressive mechanisms, and (3) repolarization towards immunostimulatory phenotypes.…”