Kwang Bog Cho

All Publications

• The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors. Cancer immunology research Pant, A., Jain, A., Chen, Y., Patel, K., Saleh, L., Tzeng, S., Nitta, R. T., Zhao, L., Wu, C. Y., Bederson, M., Wang, W. L., Bergsneider, B. H., Choi, J., Medikonda, R., Verma, R., Cho, K. B., Kim, L. H., Kim, J. E., Yazigi, E., Lee, S. Y., Rajendran, S., Rajappa, P., Mackall, C. L., Li, G., Tyler, B., Brem, H., Pardoll, D. M., Lim, M., Jackson, C. M. 2024

  Abstract

  Regulatory T cells (Tregs) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity towards CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wildtype mice, and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.

  View details for DOI 10.1158/2326-6066.CIR-24-0230

  View details for PubMedID 39133127

• The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function. Immunity Jackson, C. M., Pant, A., Dinalankara, W., Choi, J., Jain, A., Nitta, R., Yazigi, E., Saleh, L., Zhao, L., Nirschl, T. R., Kochel, C. M., Hwa-Lin Bergsneider, B., Routkevitch, D., Patel, K., Cho, K. B., Tzeng, S., Neshat, S. Y., Kim, Y. H., Smith, B. J., Ramello, M. C., Sotillo, E., Wang, X., Green, J. J., Bettegowda, C., Li, G., Brem, H., Mackall, C. L., Pardoll, D. M., Drake, C. G., Marchionni, L., Lim, M. 2024

  Abstract

  Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

  View details for DOI 10.1016/j.immuni.2024.07.003

  View details for PubMedID 39111315

• CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy. Oncoimmunology Pant, A., Hwa-Lin Bergsneider, B., Srivastava, S., Kim, T., Jain, A., Bom, S., Shah, P., Kannapadi, N., Patel, K., Choi, J., Cho, K. B., Verma, R., Yu-Ju Wu, C., Brem, H., Tyler, B., Pardoll, D. M., Jackson, C., Lim, M. 2024; 13 (1): 2338965

  Abstract

  Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

  View details for DOI 10.1080/2162402X.2024.2338965

  View details for PubMedID 38590799

  View details for PubMedCentralID PMC11000615

• MITOCHONDRIAL ATP BIOGENESIS REGULATED BY VDAC1 IN TMEM119+TUMOR-ASSOCIATED MICROGLIA AND MACROPHAGES MEDIATES HIGH-GRADE GLIOMA GROWTH Wu, C., Chen, Y., Lin, Y., Wei, K., Chang, K., Feng, L., Wu, A., Chen, K., Ren, A., Nitta, R., Wu, J., Pant, A., Cho, K., Mackall, C., Chuang, J., Huang, C., Li, G., Jackson, C., Chen, P., Lim, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401315

• Novel peptoid compounds that bind to cell receptor ace2 and prevent virus entry into cells Udugamasooriya, D., Guo, B., Shukla, S., Cho, K. US Patent App. 18/015,927. 2023
• Compounds for drug delivery across blood-brain barrier Guo, B., Udugamasooriya, D., Liu, X., Shukla, S., Cho, K., Xue, Z. US Patent App. 18/011,649. 2023
• A peptoid interleukin-15 receptor antagonist suppresses inflammation and arthritis in mice. Clinical & translational immunology Cho, K. B., Shukla, S. P., Kannan, M., Zhang, H., Amina, S. J., Zhou, S., Chen, Y., Molligan, J. F., Taneja, V., Mohan, C., Udugamasooriya, D. G., Guo, B. 2022; 11 (11): e1432

  Abstract

  To discover a novel peptoid antagonist that targets the interleukin-15 (IL-15) receptor and to evaluate its therapeutic efficacy in the treatment of inflammation and arthritis.A new compound (IFRA3, interleukin-15 receptor antagonist 3) was discovered using a unique on-bead two-colour combinatorial cell screening of a peptoid library. The interaction of IFRA3 with IL-15 receptor was assessed by in vitro pull-down and thermal shift assays. The efficacy of IFRA3 in treating inflammation and arthritis was evaluated in mouse models.IFRA3Q1 (a tetrameric derivative of IFRA3) inhibited the activity of IL-15 and suppressed CTLL-2 cell proliferation (which depends on IL-15 activity). IFRA3Q1 exhibited strong in vivo anti-inflammatory activity in carrageenan-induced inflammation in mice. Furthermore, IFRA3Q1 inhibited collagen-induced arthritis in DBA/1J mice.By binding to and inhibiting the function of IL-15 receptor, IFRA3Q1 exhibited significant anti-arthritis activity. Our findings suggest that IFRA3Q1 represents a new paradigm for arthritis therapy by targeting IL-15 signalling.

  View details for DOI 10.1002/cti2.1432

  View details for PubMedID 36439637

  View details for PubMedCentralID PMC9686008

• Inhibitors of il-15 and their use in treating autoimmune/inflammatory disorders Guo, B., Udugamasooriya, G., Shukla, S., Cho, K., Zhou, S. US Patent App. 17/624,523, US 2022/0242907 A1 . 2022
• "Molecular Masks" for ACE2 to Effectively and Safely Block SARS-CoV-2 Virus Entry INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Shukla, S., Cho, K., Rustagi, V., Gao, X., Fu, X., Zhang, S., Guo, B., Udugamasooriya, D. 2021; 22 (16)

  Abstract

  Coronavirus Disease 2019 (COVID-19) remains a global health crisis, despite the development and success of vaccines in certain countries. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, uses its spike protein to bind to the human cell surface receptor angiotensin-converting enzyme 2 (ACE2), which allows the virus to enter the human body. Using our unique cell screening technology, we identified two ACE2-binding peptoid compounds and developed dimeric derivatives (ACE2P1D1 and ACE2P2D1) that effectively blocked spike protein-ACE2 interaction, resulting in the inhibition of SARS-CoV-2 pseudovirus entry into human cells. ACE2P1D1 and ACE2P2D1 also blocked infection by a D614G mutant pseudovirus. More importantly, these compounds do not decrease ACE2 expression nor its enzyme activity (which is important in normal blood pressure regulation), suggesting safe applicability in humans.

  View details for DOI 10.3390/ijms22168963

  View details for Web of Science ID 000689201200001

  View details for PubMedID 34445669

  View details for PubMedCentralID PMC8396575

• A CRISPR-Cas9 repressor for epigenetic silencing of KRAS PHARMACOLOGICAL RESEARCH Liu, J., Sun, M., Cho, K., Gao, X., Guo, B. 2021; 164: 105304

  Abstract

  KRAS is one of the most frequently mutated oncogenes in cancers. Currently no direct and effective anti-KRAS therapies are available. Using the powerful CRISPR-Cas9 technology to target the mutant KRAS promoter, we designed an epigenetic repressor to silence KRAS through epigenome editing. Catalytically dead Cas9 (dCas9) functioned as a DNA binding device, which was fused with a transcriptional repressor histone deacetylase 1 (HDAC1). We designed a panel of three CRISPR RNAs (crRNAs) covering 1500-bp range of the KRAS promoter and identified that crRNA1 and crRNA2 efficiently silenced KRAS. The suppression of K-Ras resulted in a significant inhibition of cell growth, suppression of colony formation in soft agar and induction of cell death in cancer cells with KRAS mutations. In addition, the chromatin immunoprecipitation (ChIP) assay demonstrated dCas9-HDAC1 modified histone acetylation on the KRAS promoter. Furthermore, transfection of dCas9-HDAC1 protein and gRNA ribonucleoprotein complex also inhibited K-Ras and suppressed cell proliferation. In summary, we have developed a new strategy that combines CRISPR-Cas9 technology with HDAC1 epigenetic silencing to target cancers driven by KRAS mutations.

  View details for DOI 10.1016/j.phrs.2020.105304

  View details for Web of Science ID 000615153300004

  View details for PubMedID 33202255

  View details for PubMedCentralID PMC8422974

• Chemopreventive Agent 3,3 '-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Gao, X., Liu, J., Cho, K., Kedika, S., Guo, B. 2020; 21 (13)

  Abstract

  3,3'-Diindolylmethane (DIM) is a naturally derived chemopreventive compound. It comes from glucobrassicin, an indole glucosinolate enriched in cruciferous vegetables, and is formed in the acidic environment of the stomach after ingestion. Mouse double minute 2 homolog (MDM2) is an important, multi-functional oncogenic protein and it has been well recognized for its negative regulation of the tumor suppressor protein p53. We discovered a novel mechanism of action of DIM, that it directly inhibits MDM2 in multiple colorectal cancer (CRC) cell lines. Treatment with DIM decreased MDM2 at messenger RNA (mRNA) and protein levels, inhibited cancer cell proliferation, and induced cell cycle arrest and apoptosis. DIM-induced decrease of MDM2 is p53-independent and is partly mediated by proteasome degradation of MDM2, as blocking of the proteasome activity reversed MDM2 protein inhibition. Overexpression of MDM2 blocked DIM's effects in growth suppression and apoptosis induction. When combined with imidazoline MDM2 inhibitors (Nutlin-3a and Idasanutlin/RG-7388), synergism was observed in cancer cell growth inhibition. In summary, our data support a new mechanism of action for DIM in direct inhibition of MDM2. The identification of MDM2 as a novel DIM target may help develop a new strategy in CRC prevention.

  View details for DOI 10.3390/ijms21134642

  View details for Web of Science ID 000550262200001

  View details for PubMedID 32629830

  View details for PubMedCentralID PMC7370074

• Long Noncoding RNA (lncRNA)-Mediated Competing Endogenous RNA Networks Provide Novel Potential Biomarkers and Therapeutic Targets for Colorectal Cancer INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Wang, L., Cho, K., Li, Y., Tao, G., Xie, Z., Guo, B. 2019; 20 (22)

  Abstract

  Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs (miRNAs) and protein-coding mRNAs. LncRNAs function as competitive endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thus sequestering the miRNAs and changing the expression of their downstream target genes. Such ceRNA networks formed by lncRNA/miRNA/mRNA interactions have been found in a broad spectrum of biological processes in CRC, including liver metastasis, epithelial to mesenchymal transition (EMT), inflammation formation, and chemo-/radioresistance. In this review, we summarize typical paradigms of lncRNA-associated ceRNA networks, which are involved in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the competitive crosstalk among RNA transcripts and the novel targets for CRC prognosis and therapy.

  View details for DOI 10.3390/ijms20225758

  View details for Web of Science ID 000502786800240

  View details for PubMedID 31744051

  View details for PubMedCentralID PMC6888455

• Suppression of Mammary Carcinogenesis Through Early Exposure to Dietary Lipotropes Occurs Primarily In Utero NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Mabasa, L., Cho, K., Choi, W., Crane, C. L., Cho, K., Singh, R. K., Park, C. S. 2015; 67 (8): 1276-1282

  Abstract

  The study determined whether feeding during lactation affects the suppressive effect of maternal dietary lipotropes (i.e., methionine, choline, folate, and vitamin B12) on mammary carcinogenesis. Pregnant Sprague-Dawley rats were randomly allocated to the control diet during pregnancy and lactation (CC), lipotropes-fortified diet during pregnancy (LC), lipotropes-fortified diet during pregnancy plus lactation (LL), or lipotropes-fortified diet during lactation (CL). Randomly selected female offspring from each group were injected intraperitoneally with 50 mg/kg body weight of N-nitroso-N-methylurea at 50 days of age to induce mammary tumors. The LC and LL diets significantly increased tumor latency and survival (P < 0.05). Tumor volumes were significantly suppressed in LC and LL offspring as compared with the CC and CL pups (3759.1 ± 563.0 and 3603.7 ± 526.1 vs. 7465.0 ± 941.1 and 5219.3 ± 759.8 mm(3), respectively; P < 0.05). Both LC and LL lowered tumor multiplicity as compared with CC and CL (P < 0.05). The LC and LL diets repressed transcription of histone deacetylase (HDAC) 1 as well as total HDAC enzyme activity as compared with CC and CL diets (P < 0.05). Data suggest that the tumor suppressive effect of maternal dietary lipotropes is primarily in utero and may be linked to regulation of proteins involved in chromatin remodeling.

  View details for DOI 10.1080/01635581.2015.1087039

  View details for Web of Science ID 000365670700010

  View details for PubMedID 26474214

• In utero exposure to dietary lipotropes affects DNA methylation and gene expression in mammary glands of offspring Cho, K., Mabasa, L., Cho, K., Crane, C., Choi, W., Park, C. FEDERATION AMER SOC EXP BIOL. 2014

  View details for Web of Science ID 000346651000229