Evolutionary Pressure against MHC Class II Binding Cancer Mutations

Pyke, Rachel Marty; Thompson, Wesley K.; Salem, Rany M.; Font-Burgada, Joan; Zanetti, Maurizio; Carter, Hannah

doi:10.1016/j.cell.2018.08.048

Cited by 173 publications

(110 citation statements)

References 64 publications

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“…However, in B-cell lymphoma, tumor antigens may also be presented in MHC class II and recognized by CD4 T-cells that drive an anti-tumor immune response 9,10 . The active suppression of MHC class II expression in B-cell lymphoma may therefore be driven by evolutionary pressure against MHC class II-binding tumor antigens, in line with that recognized in other cancers 11 . In support of this notion, the reduced expression of MHC class II has been found to be associated with poor outcome in DLBCL 12 .…”

Section: Introductionmentioning

confidence: 84%

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

Mondello

Tadros

Teater

et al. 2019

Preprint

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45 46CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its 47 histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that 48 these two classes of mutations yield different degrees of disruption of the epigenome, 49 with HAT mutations being more severe and associated with inferior clinical outcome. 50 Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-51 repressor complex. Accordingly, we show that HDAC3 selective inhibitors fully reverse 52 CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of 53 lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) 54 restoration of immune surveillance due to induction of BCL6 repressed IFN pathway and 55 antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored 56 the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I 57 dependent manner. Hence HDAC3-i represent a novel mechanism-based immune-58 epigenetic therapy for CREBBP mutant lymphomas. 59 60 61 62 We have leveraged the molecular characterization of different types of CREBBP 63 mutations to define a rational approach for targeting these mutations through selective 64 inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting 65 synthetic vulnerabilities in CREBBP mutant cells in tandem with promoting anti-tumor 66 immunity. 67 68 69 70 Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most 71 frequent subtypes of non-Hodgkin lymphoma. These diseases originate from germinal 72 center B (GCB)-cells; a stage of development that naturally allows for the proliferation 73 and affinity maturation of antigen-experienced B-cells to produce terminally-differentiated 74 memory B-cells or plasma cells. The germinal center (GC) reaction is regulated by B-cell-75 intrinsic activation and suppression of large sets of genes by master regulators such as 76 the BCL6 transcription factor 1 , and extrinsically via the interaction of GCB-cells with 77 follicular helper T (TFH)-cells and other immune cells within the GC 2 . The BCL6 78 transcription factor is critical for GCB-cell development and coordinately suppresses the 79 expression of large sets of genes by recruiting SMRT and NCOR co-repressor complexes 80 containing HDAC3 3 and tethering a non-canonical polycomb repressor 1-like complex in 81 cooperation with EZH2 4 . These genes are normally reactivated to drive GC exit and 82 terminal differentiation, but the epigenetic control of these dynamically-regulated GC 83 transcriptional programs is perturbed in DLBCL and FL via the downstream effects of 84 somatic mutation of chromatin modifying genes 5 (CMG). 85 86 STATEMENT OF SIGNIFICANCEThe second most frequently mutated CMG in both DLBCL and FL is the CREBBP gene, 87 which encodes a histone acetyltransferase that activates transcription via acetylation of 88 histone H3 lysine 27 (H3K27Ac) and other residues. We have previously fo...

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Section: Introductionmentioning

confidence: 84%

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

Mondello

Tadros

Teater

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Interestingly, CD4 + T cells appeared to be more sensitive than CD8 + T cells to immune status changes. Previous studies emphasized the central role of MHC‐II presentation in tumor evolution . CD4 + T cells recognize most of the immunogenic mutanome; in neoantigen vaccination murine models, CD4 + T cell responses to neoantigens are more prevalent and potentially more effective in antitumor immunity than CD8 + T cell responses .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies emphasized the central role of MHC-II presentation in tumor evolution. 26 CD4 + T cells recognize most of the immunogenic mutanome; in neoantigen vaccination murine models, CD4 + T cell responses to neoantigens are more prevalent and potentially more effective in antitumor immunity than CD8 + T cell responses. 27 This may be because of the less stringent length and sequence requirement for peptides binding to MHC class II molecules as compared to those binding to MHC class I epitopes, increasing the likelihood that a given mutation is found within a presented peptide.…”

Section: Discussionmentioning

confidence: 99%

Pegylated recombinant human granulocyte colony‐stimulating factor regulates the immune status of patients with small cell lung cancer

et al. 2020

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Background Small cell lung cancer (SCLC) is an aggressive disease involving immunodeficiency for which chemotherapy is the standard treatment. Pegylated recombinant human granulocyte colony‐stimulating factor (PEG‐rhG‐CSF) is widely used for primary or secondary prophylaxis of febrile neutropenia (FN) in chemotherapy. However, whether PEG‐rhG‐CSF influences immune cells, such as lymphocytes, remains unclear. Methods A total of 17 treatment‐naïve SCLC patients were prospectively enrolled and divided into the PEG‐rhG‐CSF and control groups according to their FN risk. Longitudinal sampling of peripheral blood was performed before, after and 4–6 days after the first cycle of chemotherapy. Flow cytometry was used to assess lymphocyte subsets, including CD3+ T, CD4+ T, CD8+ T, NK, and B cells. The diversity and clonality of the T‐cell receptor (TCR) repertoire was analyzed by next‐generation sequencing. Results In the PEG‐rhG‐CSF group, the proportions of CD3+ T and CD4+ T cells had increased significantly (P = 0.002, P = 0.020, respectively), whereas there was no increase in CD8+ T cells. Further, TCR diversity increased (P = 0.009) and clonality decreased (P = 0.004) significantly after PEG‐rhG‐CSF treatment. However, these factors showed opposite trends before and after chemotherapy. Vβ and Jβ gene fragment types, which determine TCR diversity, were significantly amplified in the PEG‐rhG‐CSF group. The change in TCR diversity was significantly correlated with changes in the CD3+ T or CD4+ T cell proportions, but not the CD8+ T cell proportion. Conclusions PEG‐rhG‐CSF regulates the immune status of SCLC patients; CD4+ T cells may be the main effector cells involved in this process. These findings may optimize the treatment of SCLC. Key points PEG‐rhG‐CSF regulates SCLC immunity. PEG‐rhG‐CSF increased CD3+ T and CD4+T cell proportions. PEG‐rhG‐CSF increased TCR diversity and decreased clonality in peripheral blood. Change in TCR diversity were correlated with CD3+ T or CD4+ T changes.

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“… 31–33 Indeed, a group of human and murine melanoma neopeptides that binds selectively to MHCII and/or HLA-DQ alleles and activates CD4+ T cells was recently unearthed via high throughput epitope mining. 34–37 To our knowledge, humanized MHCII transgenic mice including the humanized HLA-DQ8 model have not been previously exploited to examine the effect of SAgs and/or tumor neopeptides in antitumor therapy.…”

Section: Introductionmentioning

confidence: 99%

Endogenous HLA-DQ8αβ programs superantigens (SEG/SEI) to silence toxicity and unleash a tumoricidal network with long-term melanoma survival

Knopick

Terman²,

Riha

et al. 2020

J Immunother Cancer

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BackgroundAs the most powerful T cell agonists known, superantigens (SAgs) have enormous potential for cancer immunotherapy. Their development has languished due to high incidence (60%–80%) of seroreactive neutralizing antibodies in humans and tumor necrosis factor-α (TNFα)-mediated cardiopulmonary toxicity. Such toxicity has narrowed their therapeutic index while neutralizing antibodies have nullified their therapeutic effects.MethodsFemale HLA-DQ8 (DQA*0301/DQB*0302) tg mice expressing the human major histocompatibility complex II (MHCII) HLA-DQ8 allele on a high proportion of PBL, spleen and lymph node cells were used. In the established tumor model, staphylococcal enterotoxin G and staphylococcal enterotoxin I (SEG/ SEI) (50 µg each) were injected on days 6 and 9 following tumor inoculation. Lymphoid, myeloid cells and tumor cell digests from tumor tissue were assayed using flow cytometry or quantitated using a cytometric bead array. Tumor density, necrotic and viable areas were quantitated using the ImageJ software.ResultsIn a discovery-driven effort to address these problems we introduce a heretofore unrecognized binary complex comprizing SEG/SEI SAgs linked to the endogenous human MHCII HLA-DQ8 allele in humanized mice. By contrast to staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin B (SEB) deployed previously in clinical trials, SEG and SEI does not exhibit neutralizing antibodies in humans or TNFα-mediated toxicity in humanized HLA-DQ8 mice. In the latter model wherein SAg behavior is known to be ‘human-like’, SEG/SEI induced a powerful tumoricidal response and long-term survival against established melanoma in 82% of mice. Other SAgs deployed in the same model displayed toxic shock. Initially, HLA-DQ8 mediated melanoma antigen priming, after which SEG/SEI unleashed a broad CD4+ and CD8+ antitumor network marked by expansion of melanoma reactive T cells and interferon-γ (IFNy) in the tumor microenvironment (TME). SEG/SEI further initiated chemotactic recruitment of tumor reactive T cells to the TME converting the tumor from ‘cold’ to a ‘hot’. Long-term survivors displayed remarkable resistance to parental tumor rechallenge along with the appearance of tumor specific memory and tumor reactive T memory cells.ConclusionsCollectively, these findings show for the first time that the SEG/SEI-(HLA-DQ8) empowers priming, expansion and recruitment of a population of tumor reactive T cells culminating in tumor specific memory and long-term survival devoid of toxicity. These properties distinguish SEG/SEI from other SAgs used previously in human tumor immunotherapy. Consolidation of these principles within the SEG/SEI-(HLA-DQ8) complex constitutes a conceptually new therapeutic weapon with compelling translational potential.

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Evolutionary Pressure against MHC Class II Binding Cancer Mutations

Cited by 173 publications

References 64 publications

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

Pegylated recombinant human granulocyte colony‐stimulating factor regulates the immune status of patients with small cell lung cancer

Endogenous HLA-DQ8αβ programs superantigens (SEG/SEI) to silence toxicity and unleash a tumoricidal network with long-term melanoma survival

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