Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas

Abstract

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and T reg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1expressing tumor-associated macrophages to overcome resistance to ICB.

TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme—Future Perspectives

“…TLR signaling promotes the overexpression of CD80, enhancing the presentation of antigens. It strengthens CTLR-4-induced T-cell anergy and GBM expansion [111][112][113][114].…”

Tracking the Genetic Susceptibility Background of B-Cell Non-Hodgkin’s Lymphomas from Genome-Wide Association Studies

“…GWAS have been also widely used for non-HLA alleles associations, more remarkably susceptibility risk have been found in different studies for: PVT1 (rs4733601 and rs13255292) in three different GWAS studies in which one also found to be associated with MS risk ( p = 5 × 10 −8 ); EXOC2 (rs116446171) [ 11 , 31 , 32 ] and CD86 (rs2681416 and rs9831894) [ 32 , 36 ]. PVT1 is a non-coding RNA affecting MYC activation, a driver gene in lymphomas; EXOC2 functions at the interface between host defense and cell death regulation and CD86 is well known for its role in T-cell activation [ 32 , 37 ]. Other, implicated loci are 2p23.3 ( NCOA1 ), 3p24.1 ( EOMES-AZI2 ), 5q31.3 ( ARAP3 ) and 3q27 ( BCL6-LPP ); interestingly the BCL6 has been vastly documented to be involved in B-cell lymphomagenesis due to its role as critical regulator of germinal centers and rs6773363 ( EOMES-AZI2) is indirectly involved in the activation of the NF-κB signaling pathway [ 32 , 36 , 38 ].…”

Acquired Resistance to Immune Checkpoint Blockade Therapies

“…The main driver for this type of acquired resistance is the small proportion of tumor cells that are resistant to ICBT from the onset of treatment. This hypothesis is supported by two recent publications showing that the highly heterogeneous nature of both tumor cell populations and tumor microenvironmental components creates different compartments within the tumor tissue, each with diverse sensitivities to T-cell killing [78,79]. Resistance due to this mechanism may be avoided by designing combination therapies which eliminate multiple tumor cell subclones from the start of treatment.…”