Background: Recently, molecular classification is gradually applied to systemic diffuse large B c... more Background: Recently, molecular classification is gradually applied to systemic diffuse large B cell lymphoma (DLBCL) for predicting prognosis and targeted therapy. Still, little is known about molecular classification and its clinicopathologic impacts in primary CNS-DLBCL (PCNS-DLBCL). Methods: Next genetic sequencing (NGS) and then LymphGen classification were done in 62 PCNS-DLBCL patients with homogenous R-MVP therapy. Immunohistochemistry of CD8, FOXP3, PD-1, CD68, CD163 and PD-L1 was performed and enumeration of CD8+, Foxp3+ and PD-1+ tumor infiltrating lymphocytes (TILs) and CD68+ and CD163+ macrophages was done by Aperio ImageScope 12.4.3. Tumoral PD-L1 expression was manually evaluated. Results: One A53, 1 EZB, 1 ST2, 2 MCD/A53, 43 MCD and 14 other (unclassified) subtypes were identified. As expected, MCD subtype was predominant in PCNS-DLBCL (69.4%). MCD and MCD/A53 subtypes were correlated with older age (P=0.001), higher MSKCC class (2-3) (P=0.014), and tumor multiplicity (P=0.004), compared to non-MCD subtypes. However, there was no significant difference in progression-free survival (PFS) and overall survival (OS) between two groups. Other clinicopathologic parameters including sex, performance status, B symptom, elevated LDH, ocular or multiple involvement and Ki-67 labeling index showed no significant difference between two groups. In addition, CD8+ TILs, PD-1+ TILs, FOXP3+ TILs, FOXP3+/CD8+ ratio, PD-1+/CD8+ ratio, CD68+, CD163+ and tumoral PD-L1 expression were not different according to molecular subtype. Of note, tumoral PD-1 expression was found in 16.7% of PCNS-DLBCLs including MCD (4/36, 11.1%) and non-MCD subtypes (4/12, 33.3%), which was much higher than systemic DLBCL (6/121, 4.96% in our previous data). Cases with tumoral PD-1 expression showed worse PFS than others (P=0.029). At single gene alteration level, both of MYD88L265P and CD79B mutation and BCL7A mutation tended to be related to poor PFS (P=0.067 and P=0.105, respectively). CDKN2A deletion, TP53 mutation and CD79A mutation tended to be related to poor OS (P=0.075, P=0.104, and P=0.107, respectively). Conclusions: This is the first reporting molecular classification and their clinical significance in PCNS-DLBCL of Asian population. MCD subtype was prevalent but has no prognostic power in PCNS-DLBCL. Further larger study is needed. Citation Format: Sehui Kim, Jeemin Yim, Bogyeong Han, Sung-Hye Park, Jiwon Koh, Hongseok Yun, Tae Min Kim, Yoon Kyung Jeon. Comparative analysis of clinicopathologic features and tumor immune-microenvironment of primary diffuse large B cell lymphoma of the central nervous system according to molecular classification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1402.
The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to ha... more The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to have anti-tumor activity by activating the innate immune response against cytosolic double-stranded DNA (dsDNA). The regulating mechanism of STING remains unclear, and a pro-tumorigenic effect of STING pathway was recently reported. In this study, we investigated the expression of STING by MET and a novel role of the STING pathway in non-small cell lung cancer (NSCLC). The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) analysis showed that cGAS/STING pathway is enriched and STING expression is higher in MET-overexpressing tumors. Western blot for NSCLC cells and immunohistochemistry for NSCLC tumor tissues showed positive correlation between MET and STING expression in NSCLC cells. MET-overexpression and a MET agonist (HGF) treatment increased STING expression and CXCL10 and IFNβ expression and secretion, whereas MET-knockdown and a MET inhibitor (capmatinib) treatment decreased STING expression in NSCLC cells. In MET-positive and STING-positive cells, a STING agonist (poly-dAdT and diABZI) treatment led to increased activation of STING signaling pathway. In EBC-1 cells, MET knockdown decreased STING expression and STING-agonist-induced STING-pathway activation and cytokine production. To further investigate the role STING in NSCLC, EBC-1 cells were transfected with STING siRNA and submitted to RNS-seq. Gene set enrichment analysis revealed that several pathways were affected by STING expression. Epithelial-mesenchymal transition (EMT) and TNFα-signaling via NF-κB signaling were significantly downregulated in STING-knockdowned cells. In vitro experiments using EBC-1 cells, STING overexpression increased SLUG and TWIST1 expression and migration of cells, whereas STING knockdown decreased SLUG and TWIST1 expression and migration of cells. In summary, this study demonstrated that MET and STING expression were positively correlated with each other in NSCLC and MET overexpression increased STING expression and subsequent activation upon STING agonist stimulation. In addition, STING contributed to EMT in NSCLC. Citation Format: Seungchan Mun, Bogyeong Han, HyunKyung Ahn, Jaemoon Koh, Sehui Kim, DooHyun Chung, YoonKyung Jeon. MET-mediated STING activation regulates EMT and NF-ΚB pathway in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3600.
Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of c... more Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of current immunotherapies. VTCN1 (B7-H4/B7x/B7S1) and HHLA2 (B7-H7/B7y) are B7 family co-inhibitory molecules reported to be expressed in PD-L1-negative or EGFR-mutant lung adenocarcinoma (LUAD). To elucidate the clinicopathological implications of these two immune checkpoints, we checked their detailed expression patterns including intratumoral heterogeneity. Methods: VTCN1 and HHLA2 expression were evaluated in public single-cell RNA sequencing (scRNAseq) and The Cancer Genome Atlas (TCGA) dataset. Their immunohistochemistry (IHC) was performed on tissue microarrays of 413 LUAD and 382 lung squamous cell carcinoma (LUSC) specimens. Intratumoral heterogeneity was evaluated by IHC on representative sections of 59 surgically resected LUAD and 49 LUSC specimens. Results: In LUAD scRNAseq, VTCN1 and HHLA2 were predominantly expressed on epithelial cells and were not co-expressed with PD-L1. However, IHC showed their expression in both tumor and immune cells. In TCGA analysis, there was a negative correlation between VTCN1 and PD-L1 (LUAD, r = -0.094, p = 0.033; LUSC, r = -0.227, p <0.001). VTCN1 and HHLA2 showed positive correlations in both TCGA (LUAD, r = 0.211, p <0.001; LUSC, r = 0.182, p <0.001) and IHC analysis (LUAD, p <0.001; LUSC, p = 0.016). They were more frequently expressed in EGFR-mutant LUAD (52.9% vs. 40.3%, p = 0.015 for VTCN1 in EGFR-mutant vs. wildtype; 59.8% vs. 40.5%, p <0.001 for HHLA2). CD8+ T-cell infiltration was significantly higher in VTCN1- or HHLA2-positive EGFR-mutant LUAD, but there was no significant relationship in EGFR-wildtype. In 60% of cases expressing both VTCN1 and HHLA2, the two showed spatially concordant expression (15 out of 24 LUAD; 3 out of 6 LUSC). However, VTCN1 and PD-L1 showed concordant expression in 37.2% of cases expressing both (6 out of 16 LUAD; 10 out of 27 LUSC). HHLA2 expression was associated with better overall survival in LUSC, but there was no significant difference in survival according to VTCN1 expression. Conclusions: VTCN1 and HHLA2 are frequently co-expressed in PD-L1-negative NSCLC, especially EGFR-mutant LUAD rich in CD8+ T-cells and can serve as potential novel immunotherapeutic targets. Citation Format: Sojung Lim, Jaemoon Koh, Seung Geun Song, Jeemin Yim, Bogyeong Han, Young A Kim, Doo Hyun Chung, Yoon Kyung Jeon. Expression pattern and clinicopathological implication of B7 family immune checkpoints, VTCN1 and HHLA2, in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6656.
Background: Recently, molecular classification is gradually applied to systemic diffuse large B c... more Background: Recently, molecular classification is gradually applied to systemic diffuse large B cell lymphoma (DLBCL) for predicting prognosis and targeted therapy. Still, little is known about molecular classification and its clinicopathologic impacts in primary CNS-DLBCL (PCNS-DLBCL). Methods: Next genetic sequencing (NGS) and then LymphGen classification were done in 62 PCNS-DLBCL patients with homogenous R-MVP therapy. Immunohistochemistry of CD8, FOXP3, PD-1, CD68, CD163 and PD-L1 was performed and enumeration of CD8+, Foxp3+ and PD-1+ tumor infiltrating lymphocytes (TILs) and CD68+ and CD163+ macrophages was done by Aperio ImageScope 12.4.3. Tumoral PD-L1 expression was manually evaluated. Results: One A53, 1 EZB, 1 ST2, 2 MCD/A53, 43 MCD and 14 other (unclassified) subtypes were identified. As expected, MCD subtype was predominant in PCNS-DLBCL (69.4%). MCD and MCD/A53 subtypes were correlated with older age (P=0.001), higher MSKCC class (2-3) (P=0.014), and tumor multiplicit...
Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of c... more Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of current immunotherapies. VTCN1 (B7-H4/B7x/B7S1) and HHLA2 (B7-H7/B7y) are B7 family co-inhibitory molecules reported to be expressed in PD-L1-negative or EGFR-mutant lung adenocarcinoma (LUAD). To elucidate the clinicopathological implications of these two immune checkpoints, we checked their detailed expression patterns including intratumoral heterogeneity. Methods: VTCN1 and HHLA2 expression were evaluated in public single-cell RNA sequencing (scRNAseq) and The Cancer Genome Atlas (TCGA) dataset. Their immunohistochemistry (IHC) was performed on tissue microarrays of 413 LUAD and 382 lung squamous cell carcinoma (LUSC) specimens. Intratumoral heterogeneity was evaluated by IHC on representative sections of 59 surgically resected LUAD and 49 LUSC specimens. Results: In LUAD scRNAseq, VTCN1 and HHLA2 were predominantly expressed on epithelial cells and were not co-expressed with PD-L1. Ho...
The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to ha... more The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to have anti-tumor activity by activating the innate immune response against cytosolic double-stranded DNA (dsDNA). The regulating mechanism of STING remains unclear, and a pro-tumorigenic effect of STING pathway was recently reported. In this study, we investigated the expression of STING by MET and a novel role of the STING pathway in non-small cell lung cancer (NSCLC). The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) analysis showed that cGAS/STING pathway is enriched and STING expression is higher in MET-overexpressing tumors. Western blot for NSCLC cells and immunohistochemistry for NSCLC tumor tissues showed positive correlation between MET and STING expression in NSCLC cells. MET-overexpression and a MET agonist (HGF) treatment increased STING expression and CXCL10 and IFNβ expression and secretion, whereas MET-knockdown and a MET inhibitor (capmatinib) treatment...
Background: T-cell factor 1 (TCF1) þ Programmed cell death-1 (PD-1) þ tumourinfiltrating lymphocy... more Background: T-cell factor 1 (TCF1) þ Programmed cell death-1 (PD-1) þ tumourinfiltrating lymphocytes (TILs) are a recently defined subset of exhausted T-cells (Texh-cells) that exhibit a progenitor phenotype. They have been associated with a response to immune checkpoint inhibitor (ICI) therapy in murine tumour models and in patients with malignant
Additional file 1: Supplementary Table 1. Somatic nonsynonymous single nucleotide variation detec... more Additional file 1: Supplementary Table 1. Somatic nonsynonymous single nucleotide variation detected by WGS in our lymphangioleiomyoma, but most were VUS except MST1 and TSC2.
Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder associated with ge... more Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder associated with germline mutations in TSC1 and TSC2, including exonic, intronic, or mosaic mutations. Gastrointestinal (GI) tract Lymphangioleiomyomatosis (LAM) is an extremely rare manifestation of TSC, with few reported cases. Herein, we aimed to determine the driver mutation, pathogenesis, and relationship of germline and somatic mutations of LAM through whole-genome sequencing (WGS) of the tumor and blood samples and whole transcriptome sequencing (WTS) analysis. Case presentation: A nine-year-old girl with a full-blown TSC presented with abdominal masses detected during a routine check-up. Resected intestinal masses were diagnosed as LAM by thorough pathological examination. Interestingly, the LAM presented a somatic TSC2 gene mutation in exon 24 (p.R905W, c.C2713T), and the patient had intron retention by a novel germline mutation in the intron region of TSC2 (chr16:2126489, C>G). Conclusion: Our...
Background: Anti-tumor immunity plays a key role in tumor development and progression and the lan... more Background: Anti-tumor immunity plays a key role in tumor development and progression and the landscape of tumor immune microenvironment could affect the clinical outcome of patients. The concept of immunoscore based on immune cell infiltration has been actively applied to solid tumors including colon cancer and malignant melanoma and successfully predicted prognosis of patients. However, a potential utility of immunoscore in predicting prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. For easy application of immunoscore to daily practice, we investigated the prognostic value of tumor-infiltrating CD3+ T-cell density which is routinely stained for diagnosing malignant lymphomas, and then explored the feasibility of immunoscore application in DLBCL. Method: One-hundred-four patients with DLBCL treated with R-CHOP therapy, whose tumors were prospectively immunoprofiled for routine clinical diagnosis, were enrolled in this study. Immunohistochemistry was...
Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status has been approved a... more Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status has been approved as a tissue-agnostic biomarker for immune checkpoint inhibitor therapy in patients with solid tumors. We report the case of an MSI-H/dMMR diffuse large B-cell lymphoma (DLBCL) identified by targeted gene sequencing (TGS). A 90-year-old female who presented with vaginal bleeding and a large mass in the upper vagina was diagnosed with germinal center-B-cell-like DLBCL, which recurred at the uterine cervix at 9 months after chemotherapy. Based on TGS of 121 lymphoma-related genes and the LymphGen algorithm, the tumor was classified genetically as DLBCL of EZB subtype. Mutations in multiple genes, including frequent frameshift mutations, were detected by TGS and further suggested MSI. The MSI-H/dMMR and loss of MLH1 and PMS2 expression were determined in MSI-fragment analysis, MSI real-time polymerase chain reaction, and immunohistochemical tests. This case demonstrates the potential diagnostic and therapeutic utility of lymphoma panel sequencing for DLBCL with MSI-H/dMMR.
Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor pro... more Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (p = 0.058). DE-DLBCL patients were older (p = 0.040) and more frequently exhibited elevated serum LDH levels (p = 0.002), higher international prognostic index (IPI; p = 0.042), non-germinal-center B-cell phenotype (p < 0.001), and poor response to therapy (p = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI (p < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; p = 0.017), involvement of ≥2 extranodal sites (p = 0.021), bone marro...
Background: Recently, molecular classification is gradually applied to systemic diffuse large B c... more Background: Recently, molecular classification is gradually applied to systemic diffuse large B cell lymphoma (DLBCL) for predicting prognosis and targeted therapy. Still, little is known about molecular classification and its clinicopathologic impacts in primary CNS-DLBCL (PCNS-DLBCL). Methods: Next genetic sequencing (NGS) and then LymphGen classification were done in 62 PCNS-DLBCL patients with homogenous R-MVP therapy. Immunohistochemistry of CD8, FOXP3, PD-1, CD68, CD163 and PD-L1 was performed and enumeration of CD8+, Foxp3+ and PD-1+ tumor infiltrating lymphocytes (TILs) and CD68+ and CD163+ macrophages was done by Aperio ImageScope 12.4.3. Tumoral PD-L1 expression was manually evaluated. Results: One A53, 1 EZB, 1 ST2, 2 MCD/A53, 43 MCD and 14 other (unclassified) subtypes were identified. As expected, MCD subtype was predominant in PCNS-DLBCL (69.4%). MCD and MCD/A53 subtypes were correlated with older age (P=0.001), higher MSKCC class (2-3) (P=0.014), and tumor multiplicity (P=0.004), compared to non-MCD subtypes. However, there was no significant difference in progression-free survival (PFS) and overall survival (OS) between two groups. Other clinicopathologic parameters including sex, performance status, B symptom, elevated LDH, ocular or multiple involvement and Ki-67 labeling index showed no significant difference between two groups. In addition, CD8+ TILs, PD-1+ TILs, FOXP3+ TILs, FOXP3+/CD8+ ratio, PD-1+/CD8+ ratio, CD68+, CD163+ and tumoral PD-L1 expression were not different according to molecular subtype. Of note, tumoral PD-1 expression was found in 16.7% of PCNS-DLBCLs including MCD (4/36, 11.1%) and non-MCD subtypes (4/12, 33.3%), which was much higher than systemic DLBCL (6/121, 4.96% in our previous data). Cases with tumoral PD-1 expression showed worse PFS than others (P=0.029). At single gene alteration level, both of MYD88L265P and CD79B mutation and BCL7A mutation tended to be related to poor PFS (P=0.067 and P=0.105, respectively). CDKN2A deletion, TP53 mutation and CD79A mutation tended to be related to poor OS (P=0.075, P=0.104, and P=0.107, respectively). Conclusions: This is the first reporting molecular classification and their clinical significance in PCNS-DLBCL of Asian population. MCD subtype was prevalent but has no prognostic power in PCNS-DLBCL. Further larger study is needed. Citation Format: Sehui Kim, Jeemin Yim, Bogyeong Han, Sung-Hye Park, Jiwon Koh, Hongseok Yun, Tae Min Kim, Yoon Kyung Jeon. Comparative analysis of clinicopathologic features and tumor immune-microenvironment of primary diffuse large B cell lymphoma of the central nervous system according to molecular classification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1402.
The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to ha... more The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to have anti-tumor activity by activating the innate immune response against cytosolic double-stranded DNA (dsDNA). The regulating mechanism of STING remains unclear, and a pro-tumorigenic effect of STING pathway was recently reported. In this study, we investigated the expression of STING by MET and a novel role of the STING pathway in non-small cell lung cancer (NSCLC). The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) analysis showed that cGAS/STING pathway is enriched and STING expression is higher in MET-overexpressing tumors. Western blot for NSCLC cells and immunohistochemistry for NSCLC tumor tissues showed positive correlation between MET and STING expression in NSCLC cells. MET-overexpression and a MET agonist (HGF) treatment increased STING expression and CXCL10 and IFNβ expression and secretion, whereas MET-knockdown and a MET inhibitor (capmatinib) treatment decreased STING expression in NSCLC cells. In MET-positive and STING-positive cells, a STING agonist (poly-dAdT and diABZI) treatment led to increased activation of STING signaling pathway. In EBC-1 cells, MET knockdown decreased STING expression and STING-agonist-induced STING-pathway activation and cytokine production. To further investigate the role STING in NSCLC, EBC-1 cells were transfected with STING siRNA and submitted to RNS-seq. Gene set enrichment analysis revealed that several pathways were affected by STING expression. Epithelial-mesenchymal transition (EMT) and TNFα-signaling via NF-κB signaling were significantly downregulated in STING-knockdowned cells. In vitro experiments using EBC-1 cells, STING overexpression increased SLUG and TWIST1 expression and migration of cells, whereas STING knockdown decreased SLUG and TWIST1 expression and migration of cells. In summary, this study demonstrated that MET and STING expression were positively correlated with each other in NSCLC and MET overexpression increased STING expression and subsequent activation upon STING agonist stimulation. In addition, STING contributed to EMT in NSCLC. Citation Format: Seungchan Mun, Bogyeong Han, HyunKyung Ahn, Jaemoon Koh, Sehui Kim, DooHyun Chung, YoonKyung Jeon. MET-mediated STING activation regulates EMT and NF-ΚB pathway in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3600.
Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of c... more Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of current immunotherapies. VTCN1 (B7-H4/B7x/B7S1) and HHLA2 (B7-H7/B7y) are B7 family co-inhibitory molecules reported to be expressed in PD-L1-negative or EGFR-mutant lung adenocarcinoma (LUAD). To elucidate the clinicopathological implications of these two immune checkpoints, we checked their detailed expression patterns including intratumoral heterogeneity. Methods: VTCN1 and HHLA2 expression were evaluated in public single-cell RNA sequencing (scRNAseq) and The Cancer Genome Atlas (TCGA) dataset. Their immunohistochemistry (IHC) was performed on tissue microarrays of 413 LUAD and 382 lung squamous cell carcinoma (LUSC) specimens. Intratumoral heterogeneity was evaluated by IHC on representative sections of 59 surgically resected LUAD and 49 LUSC specimens. Results: In LUAD scRNAseq, VTCN1 and HHLA2 were predominantly expressed on epithelial cells and were not co-expressed with PD-L1. However, IHC showed their expression in both tumor and immune cells. In TCGA analysis, there was a negative correlation between VTCN1 and PD-L1 (LUAD, r = -0.094, p = 0.033; LUSC, r = -0.227, p &lt;0.001). VTCN1 and HHLA2 showed positive correlations in both TCGA (LUAD, r = 0.211, p &lt;0.001; LUSC, r = 0.182, p &lt;0.001) and IHC analysis (LUAD, p &lt;0.001; LUSC, p = 0.016). They were more frequently expressed in EGFR-mutant LUAD (52.9% vs. 40.3%, p = 0.015 for VTCN1 in EGFR-mutant vs. wildtype; 59.8% vs. 40.5%, p &lt;0.001 for HHLA2). CD8+ T-cell infiltration was significantly higher in VTCN1- or HHLA2-positive EGFR-mutant LUAD, but there was no significant relationship in EGFR-wildtype. In 60% of cases expressing both VTCN1 and HHLA2, the two showed spatially concordant expression (15 out of 24 LUAD; 3 out of 6 LUSC). However, VTCN1 and PD-L1 showed concordant expression in 37.2% of cases expressing both (6 out of 16 LUAD; 10 out of 27 LUSC). HHLA2 expression was associated with better overall survival in LUSC, but there was no significant difference in survival according to VTCN1 expression. Conclusions: VTCN1 and HHLA2 are frequently co-expressed in PD-L1-negative NSCLC, especially EGFR-mutant LUAD rich in CD8+ T-cells and can serve as potential novel immunotherapeutic targets. Citation Format: Sojung Lim, Jaemoon Koh, Seung Geun Song, Jeemin Yim, Bogyeong Han, Young A Kim, Doo Hyun Chung, Yoon Kyung Jeon. Expression pattern and clinicopathological implication of B7 family immune checkpoints, VTCN1 and HHLA2, in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6656.
Background: Recently, molecular classification is gradually applied to systemic diffuse large B c... more Background: Recently, molecular classification is gradually applied to systemic diffuse large B cell lymphoma (DLBCL) for predicting prognosis and targeted therapy. Still, little is known about molecular classification and its clinicopathologic impacts in primary CNS-DLBCL (PCNS-DLBCL). Methods: Next genetic sequencing (NGS) and then LymphGen classification were done in 62 PCNS-DLBCL patients with homogenous R-MVP therapy. Immunohistochemistry of CD8, FOXP3, PD-1, CD68, CD163 and PD-L1 was performed and enumeration of CD8+, Foxp3+ and PD-1+ tumor infiltrating lymphocytes (TILs) and CD68+ and CD163+ macrophages was done by Aperio ImageScope 12.4.3. Tumoral PD-L1 expression was manually evaluated. Results: One A53, 1 EZB, 1 ST2, 2 MCD/A53, 43 MCD and 14 other (unclassified) subtypes were identified. As expected, MCD subtype was predominant in PCNS-DLBCL (69.4%). MCD and MCD/A53 subtypes were correlated with older age (P=0.001), higher MSKCC class (2-3) (P=0.014), and tumor multiplicit...
Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of c... more Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of current immunotherapies. VTCN1 (B7-H4/B7x/B7S1) and HHLA2 (B7-H7/B7y) are B7 family co-inhibitory molecules reported to be expressed in PD-L1-negative or EGFR-mutant lung adenocarcinoma (LUAD). To elucidate the clinicopathological implications of these two immune checkpoints, we checked their detailed expression patterns including intratumoral heterogeneity. Methods: VTCN1 and HHLA2 expression were evaluated in public single-cell RNA sequencing (scRNAseq) and The Cancer Genome Atlas (TCGA) dataset. Their immunohistochemistry (IHC) was performed on tissue microarrays of 413 LUAD and 382 lung squamous cell carcinoma (LUSC) specimens. Intratumoral heterogeneity was evaluated by IHC on representative sections of 59 surgically resected LUAD and 49 LUSC specimens. Results: In LUAD scRNAseq, VTCN1 and HHLA2 were predominantly expressed on epithelial cells and were not co-expressed with PD-L1. Ho...
The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to ha... more The cyclic GAMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to have anti-tumor activity by activating the innate immune response against cytosolic double-stranded DNA (dsDNA). The regulating mechanism of STING remains unclear, and a pro-tumorigenic effect of STING pathway was recently reported. In this study, we investigated the expression of STING by MET and a novel role of the STING pathway in non-small cell lung cancer (NSCLC). The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) analysis showed that cGAS/STING pathway is enriched and STING expression is higher in MET-overexpressing tumors. Western blot for NSCLC cells and immunohistochemistry for NSCLC tumor tissues showed positive correlation between MET and STING expression in NSCLC cells. MET-overexpression and a MET agonist (HGF) treatment increased STING expression and CXCL10 and IFNβ expression and secretion, whereas MET-knockdown and a MET inhibitor (capmatinib) treatment...
Background: T-cell factor 1 (TCF1) þ Programmed cell death-1 (PD-1) þ tumourinfiltrating lymphocy... more Background: T-cell factor 1 (TCF1) þ Programmed cell death-1 (PD-1) þ tumourinfiltrating lymphocytes (TILs) are a recently defined subset of exhausted T-cells (Texh-cells) that exhibit a progenitor phenotype. They have been associated with a response to immune checkpoint inhibitor (ICI) therapy in murine tumour models and in patients with malignant
Additional file 1: Supplementary Table 1. Somatic nonsynonymous single nucleotide variation detec... more Additional file 1: Supplementary Table 1. Somatic nonsynonymous single nucleotide variation detected by WGS in our lymphangioleiomyoma, but most were VUS except MST1 and TSC2.
Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder associated with ge... more Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder associated with germline mutations in TSC1 and TSC2, including exonic, intronic, or mosaic mutations. Gastrointestinal (GI) tract Lymphangioleiomyomatosis (LAM) is an extremely rare manifestation of TSC, with few reported cases. Herein, we aimed to determine the driver mutation, pathogenesis, and relationship of germline and somatic mutations of LAM through whole-genome sequencing (WGS) of the tumor and blood samples and whole transcriptome sequencing (WTS) analysis. Case presentation: A nine-year-old girl with a full-blown TSC presented with abdominal masses detected during a routine check-up. Resected intestinal masses were diagnosed as LAM by thorough pathological examination. Interestingly, the LAM presented a somatic TSC2 gene mutation in exon 24 (p.R905W, c.C2713T), and the patient had intron retention by a novel germline mutation in the intron region of TSC2 (chr16:2126489, C>G). Conclusion: Our...
Background: Anti-tumor immunity plays a key role in tumor development and progression and the lan... more Background: Anti-tumor immunity plays a key role in tumor development and progression and the landscape of tumor immune microenvironment could affect the clinical outcome of patients. The concept of immunoscore based on immune cell infiltration has been actively applied to solid tumors including colon cancer and malignant melanoma and successfully predicted prognosis of patients. However, a potential utility of immunoscore in predicting prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. For easy application of immunoscore to daily practice, we investigated the prognostic value of tumor-infiltrating CD3+ T-cell density which is routinely stained for diagnosing malignant lymphomas, and then explored the feasibility of immunoscore application in DLBCL. Method: One-hundred-four patients with DLBCL treated with R-CHOP therapy, whose tumors were prospectively immunoprofiled for routine clinical diagnosis, were enrolled in this study. Immunohistochemistry was...
Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status has been approved a... more Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status has been approved as a tissue-agnostic biomarker for immune checkpoint inhibitor therapy in patients with solid tumors. We report the case of an MSI-H/dMMR diffuse large B-cell lymphoma (DLBCL) identified by targeted gene sequencing (TGS). A 90-year-old female who presented with vaginal bleeding and a large mass in the upper vagina was diagnosed with germinal center-B-cell-like DLBCL, which recurred at the uterine cervix at 9 months after chemotherapy. Based on TGS of 121 lymphoma-related genes and the LymphGen algorithm, the tumor was classified genetically as DLBCL of EZB subtype. Mutations in multiple genes, including frequent frameshift mutations, were detected by TGS and further suggested MSI. The MSI-H/dMMR and loss of MLH1 and PMS2 expression were determined in MSI-fragment analysis, MSI real-time polymerase chain reaction, and immunohistochemical tests. This case demonstrates the potential diagnostic and therapeutic utility of lymphoma panel sequencing for DLBCL with MSI-H/dMMR.
Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor pro... more Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (p = 0.058). DE-DLBCL patients were older (p = 0.040) and more frequently exhibited elevated serum LDH levels (p = 0.002), higher international prognostic index (IPI; p = 0.042), non-germinal-center B-cell phenotype (p < 0.001), and poor response to therapy (p = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI (p < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; p = 0.017), involvement of ≥2 extranodal sites (p = 0.021), bone marro...
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Papers by Bogyeong Han