Significance Novel approaches to promote killing of HIV-1–infected cells are necessary for elimination of the latent reservoir, the main barrier to a cure. Here, we utilized a diverse phage-display library to construct T cell receptor (TCR)-mimic antibodies to HIV-1 peptide-major histocompatibility complexes (pMHC). We show that single-chain diabody forms of these antibodies recognize distinct epitopes in Gag and reverse transcriptase in a specific manner and induce T cell-mediated killing of HIV-1–infected CD4 + T cells. This study lays the groundwork for future exploration of pMHC-based immunotherapeutic approaches toward elimination of the latent reservoir once effective latency-reversing strategies are developed.
Cancers evade immune surveillance, which can be reversed through immune checkpoint therapy in a small subset of cases. Here we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune checkpoint expression, predicted non-responsiveness to immune checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI mediated antigen presentation, which in turn impeded T cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to recruitment of pro-inflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the anti-neoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune checkpoint responsiveness and a key driver of immune evasion through the suppression of pro-inflammatory macrophages. The immune evasion by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade.
Glioblastoma multiforme (GBM) is the most malignant form of cancer in the central nervous system; even with treatment, it has a five-year survival rate of 7.2%. The adoptive cell transfer (ACT) of T cells expressing chimeric antigen receptors (CARs) has shown a remarkable success against hematological malignancies, namely leukemia and multiple myeloma. However, CAR T cell therapy against solid tumors, and more specifically GBM, is still riddled with challenges preventing its widespread adoption. Here, we first establish the obstacles in ACT against GBM, including on-target/off-tumor toxicity, antigen modulation, tumor heterogeneity, and the immunosuppressive tumor microenvironment. We then present recent preclinical and clinical studies targeting well-characterized GBM antigens, which include the interleukin-13 receptor α2 and the epidermal growth factor receptor. Afterwards, we turn our attention to alternative targets in GBM, including less-explored antigens such as B7-H3 (CD276), carbonic anhydrase IX, and the GD2 ganglioside. We also discuss additional target ligands, namely CD70, and natural killer group 2 member D ligands. Finally, we present the possibilities afforded by novel CAR architectures. In particular, we examine the use of armored CARs to improve survival and proliferation of CAR T cells. We conclude by discussing the advantages of tandem and synNotch CARs when targeting multiple GBM antigens.
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