Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

Mondello, Patrizia; Tadros, Saber; Teater, Matt; Fontán, Lorena; Chang, Amy; Jain, Neeraj; Yang, Haopeng; Singh, Shailbala; Ying, Hsia Yuan; Chu, Chi Shuen; John, Man Chun; Toska, Eneda; Alig, Stefan; Durant, Matthew; Stanchina, Elisa de; Ghosh, Sreejoyee; Mottok, Anja; Nastoupil, Loretta J.; Neelapu, Sattva S.; Weigert, Oliver; Inghirami, Giorgio; Baselga, José; Younes, Anas; Yee, Cassian; Doğan, Ahmet; Scheinberg, David A.; Roeder, Robert G.; Melnick, Ari; Green, Michael R.

doi:10.1158/2159-8290.cd-19-0116

Cited by 120 publications

(117 citation statements)

References 49 publications

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“…These dysregulated pathways may be potential targets for improving the sensitivity to immunotherapy. Importantly, these results are in line with prior publications, which have provided some evidence that inhibition of epigenetic modification (Mondello et al, 2020) or activation of PPAR signaling pathways (Chowdhury et al, 2018;Saibil et al, 2019) might be a promising way to overcome therapeutic resistance to immune checkpoint blockade or ACT.…”

Section: Discussionsupporting

confidence: 90%

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Analysis of Gene Signatures of Tumor Microenvironment Yields Insight Into Mechanisms of Resistance to Immunotherapy

Wang

Liu

Ran

et al. 2020

Front. Bioeng. Biotechnol.

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Background: The recent clinical success of immunotherapy represents a turning point in cancer management. But the response rate of immunotherapy is still limited. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, due to the lack of appropriate experimental methods, the reason why the immunotherapeutic resistance still existed on the inflamed tumor microenvironment remains unclear. Materials and Methods: Here, based on single-cell RNA sequencing, we classified the tumor microenvironment into inflamed immunotherapeutic responsive and inflamed non-responsive. Then, phenotype-specific genes were identified to show mechanistic differences between distant microenvironment phenotypes. Finally, we screened for some potential drugs that can convert an unfavorable microenvironment phenotype to a favorable one to aid current immunotherapy. Results: Multiple signaling pathways were phenotypes-specific dysregulated. Compared to non-inflamed microenvironment, the expression of interleukin signaling pathways-associated genes was upregulated in inflamed microenvironment. Compared to inflamed responsive microenvironment, the PPAR signaling pathway-related genes and multiple epigenetic pathways-related genes were, respectively, suppressed and upregulated in the inflamed non-responsive microenvironment, suggesting a potential mechanism of immunotherapeutic resistance. Interestingly, some of the identified phenotype-specific gene signatures have shown their potential to enhance the efficacy of current immunotherapy. Conclusion: These results may contribute to the mechanistic understanding of immunotherapeutic resistance and guide rational therapeutic combinations of distant targeted chemotherapy agents with immunotherapy.

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Section: Discussionsupporting

confidence: 90%

“…As shown in Figure 6C, multiple epigenetic signaling pathways were upregulated in inflamed non-responders, which suggested a mechanism of immunotherapeutic resistance as observed by others (Mondello et al, 2020;Olino et al, 2020).…”

Section: Mechanistic Differences Between Inflamed Responsive Tme and supporting

confidence: 63%

Analysis of Gene Signatures of Tumor Microenvironment Yields Insight Into Mechanisms of Resistance to Immunotherapy

Wang

Liu

Ran

et al. 2020

Front. Bioeng. Biotechnol.

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“…It was reported that selective inhibition of HDAC3 could activate immune surveillance in lymphoma, resulting in the inhibition of lymphoma cell growth. 11 A clinical trial assessing the efficacy and safety of chidamide in patients with DLBCL in mainland China is currently underway.…”

Section: Discussionmentioning

confidence: 99%

Chidamide combined with ibrutinib improved the prognosis of primary bone marrow diffuse large B cell lymphoma

Tian

Chen

2020

J Int Med Res

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Primary bone marrow diffuse large B cell lymphoma (DLBCL) is an independent pathologic type with a poor prognosis when treated with standard chemoimmunotherapy. Generally, rituximab-based high-dose chemotherapy regimens such as dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) can be administered to young patients, followed by autologous stem cell transplantation. For elderly patients, the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen is well tolerated, but it is an insufficient induction therapy for this group. Herein, we reported an elderly patient diagnosed with primary bone marrow DLBCL, germinal center B-cell-like subtype. Considering tolerance, the R-CHOP regimen was administered. However, his disease progressed after two treatment cycles. Then, the rituximab, gemcitabine, dexamethasone, cisplatin, lenalidomide regimen was administered, but the patient still experienced disease progression. Subsequently, the histone deacetylase (HDAC) inhibitor chidamide and Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib were concurrently administered, and the patient achieved complete remission. We found that the response of primary bone marrow DLBCL to chemotherapy was poorer than that of de novo DLBCL. High-dose chemotherapy regimens such as DA-EPOCH should be administered to young patients in combination with rituximab. For elderly patients, new targeted drugs such as HDAC and BTK inhibitors appear to produce favorable outcomes.

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“…27 CREBBP mutations are associated with poor outcome in FL, 28 but KAT domain mutations are associated with a worse progression-free survival than nonsense/frameshift mutations. 11 Murine studies using Crebbp knockout (KO)/knockdown found that Crebbp loss promotes B-cell lymphoma in cooperation with Bcl2 overexpression 27,29,30 and that regions of reduced histone acetylation associated with Crebbp loss were primarily located at enhancer elements bound by BCL6. 29 Consistent with this, cKO of Crebbp in GCB cells leads to reduced expression of genes that are expressed in LZ GCB cells, such as those involved in antigen presentation on MHC class II, B-cell receptor signaling, and interferon signaling.…”

Section: Crebbp: Not All Mutations Are Created Equalmentioning

confidence: 99%

“…Key differences exist between the magnitudes of changes observed in mouse models using KO/knockdown versus primary tumors in which KAT domain mutations predominate 31 and when comparing patient outcomes by CREBBP mutational subtypes. Mondello et al 11 therefore investigated functional differences between CREBBP KAT domain mutations and nonsense/frameshift mutations. This was achieved using CRISPR/Cas9 gene editing to generate isogenic lymphoma cell lines with either wild-type CREBBP, CREBBP-R1446C mutation (a mutation hotspot in the KAT domain), or homozygous frameshift mutation (KO).…”

Section: Crebbp: Not All Mutations Are Created Equalmentioning

confidence: 99%

Harnessing lymphoma epigenetics to improve therapies (article not eligible for CME credit)

Yang¹,

Green

2020

Hematology

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Affinity maturation and terminal differentiation of B cells via the germinal center reaction is a complex multistep process controlled by transcription factors that induce or suppress large dynamic transcriptional programs. This occurs via the recruitment of coactivator or corepressor complexes that epigenetically regulate gene expression by post-translationally modifying histones and/or remodeling chromatin structure. B-cell–intrinsic developmental programs both regulate and respond to interactions with other cells in the germinal center that provide survival and differentiation signals, such as T-follicular helper cells and follicular dendritic cells. Epigenetic and transcriptional programs that naturally occur during B-cell development are hijacked in B-cell lymphoma by genetic alterations that directly or indirectly change the function of transcription factors and/or chromatin-modifying genes. These in turn skew differentiation toward the tumor cell of origin and alter interactions between lymphoma B cells and other cells within the microenvironment. Understanding the mechanisms by which genetic alterations perturb epigenetic and transcriptional programs regulating B-cell development and immune interactions may identify opportunities to target these programs using epigenetic-modifying agents. Here, we discuss recently published studies centered on follicular lymphoma and diffuse large B-cell lymphoma within the context of prior knowledge, and we highlight how these insights have informed potential avenues for rational therapeutic interventions.

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Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

Cited by 120 publications

References 49 publications

Analysis of Gene Signatures of Tumor Microenvironment Yields Insight Into Mechanisms of Resistance to Immunotherapy

Analysis of Gene Signatures of Tumor Microenvironment Yields Insight Into Mechanisms of Resistance to Immunotherapy

Chidamide combined with ibrutinib improved the prognosis of primary bone marrow diffuse large B cell lymphoma

Harnessing lymphoma epigenetics to improve therapies (article not eligible for CME credit)

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