The immune checkpoint expression in the tumor immune microenvironment of DLBCL: Clinicopathologic features and prognosis

Ma, Jiajia; Pang, Xuelian; Li, Junna; Zhang, Wei; Cui, Weigang

doi:10.3389/fonc.2022.1069378

Cited by 8 publications

(6 citation statements)

References 28 publications

(32 reference statements)

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“…Lymphocytes are important mediators of antibody-dependent cell-mediated cytotoxicity, and lymphopenia is an indicator of poor prognosis in DLBCL due to the reduced tumor clearance and surveillance ability of the host ( 19 ). An increased level of monocytes in the peripheral blood can promote tumor progression by increasing angiogenesis, inhibit anti-tumor immunity, and increase the proliferation of malignant cells ( 20 ). A low LMR favors tumorigenesis and progression by increasing the levels of cytokines released by tumor cells, such as granulocyte colony-stimulating factor.…”

Section: Discussionmentioning

confidence: 99%

Establishment and evaluation of a nomogram for predicting the survival outcomes of patients with diffuse large B-cell lymphoma based on International Prognostic Index scores and clinical indicators

Chen¹,

Xu²,

Meng³

et al. 2023

Ann Transl Med

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Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma, treatment outcomes of patients vary greatly. The current International Prognostic Index (IPI) is not enough to distinguish patients with poor prognosis, and genetic testing is very expensive, so a inexpensive risk prediction tool should be developed for clinicians to quickly identify the poor prognosis of DLBCL patients. Methods DLBCL patients (n=420; 18–80 years old) who received a combination of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) with or without rituximab (R-CHOP) at our hospital between 2008 and 2017 were included in the study. Potential predictors of survival were determined by univariate and multivariate Cox regression analyses, and significant variables were used to construct predictive nomograms. The new prediction models were assessed using concordance indexes (C-indexes), calibration curves, and their clinical utility was assessed by decision curve analyses (DCAs). Results The 5-year overall survival (OS) rate was 70.62% and the 5-year progression-free survival (PFS) rate was 59.02%. The multivariate Cox analysis indicated that IPI, Ki-67, the lymphocyte/monocyte ratio, and first-line treatment with rituximab were significantly associated with survival. The C-index results indicated that a predictive model that included these variables had better discriminability for OS (0.73 vs . 0.67) and PFS (0.68 vs . 0.63) than the IPI-based model. The calibration plots showed good agreement with observations and nomogram predictions. The DCAs demonstrated the clinical value of the nomograms. Conclusions Our study identified prognostic factors in patients who were newly diagnosed with DLBCL to construct an individualized risk prediction model, combined IPI with common clinical indicators. Our model might be a valuable tool that could be used to predict the prognosis of DLBCL patients who receive standard first-line treatment regimens. It enables clinicians to quickly identify some patients with possible poor prognosis and choose more active treatment for patients, such as chimeric antigen receptor T-cell (CART) Immunotherapy and other new drugs therapy, so as to prolong the PFS and OS of patients.

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Section: Discussionmentioning

confidence: 99%

Establishment and evaluation of a nomogram for predicting the survival outcomes of patients with diffuse large B-cell lymphoma based on International Prognostic Index scores and clinical indicators

Chen¹,

Xu²,

Meng³

et al. 2023

Ann Transl Med

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“…Another report showed the costimulatory interactions between malignant B-cells and T-cells in human DLBCL, and the coinhibitory signals mediated by immune checkpoint seemed to be the main driving force for T cell exhaustion [ 46 ]. In addition, it was reported that immune cells in the tumor microenvironment were associated with the outcome in human DLBCL [ 3 , 26 , 45 ]. The studies indicated that patient prognosis was correlated with the abundance of tumor-infiltrating T-cells and their subsets.…”

Section: Discussionmentioning

confidence: 99%

“…The studies indicated that patient prognosis was correlated with the abundance of tumor-infiltrating T-cells and their subsets. Furthermore, patients with a high percentage of immune checkpoint-positive T cells had a worse prognosis [ 3 , 26 , 45 ]. Transcriptomic analysis revealed the overexpression of immunosuppressive factors and inflammatory chemokines in relapsed/refractory DLBCL cases when compared to chemotherapy-sensitive DLBCL cases [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles associated with early relapse during first remission induction in canine multicentric high-grade B-cell lymphoma

TOYODA,

TANI,

GOTO-KOSHINO

et al. 2024

The Journal of Veterinary Medical Science

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Although chemotherapy using CHOP-based protocol induces remission in most cases of canine multicentric high-grade B-cell lymphoma (mhBCL), some cases develop early relapse during the first induction protocol. In this study, we examined the gene expression profiles of canine mhBCL before chemotherapy and investigated their associations with early relapse during the first whole CHOP-based protocol. Twenty-five cases of mhBCL treated with CHOP-based protocol as first induction chemotherapy were included in this study. Sixteen cases completed the first whole CHOP-based protocol without relapse (S-group), and nine developed relapse during the chemotherapy (R-group). RNA-seq was performed on samples from neoplastic lymph nodes. Differentially expressed genes (DEGs) were extracted by the comparison of gene expression profiles between S- and R-groups, and the differences in the expression levels of these genes were validated by RT-qPCR. Extracted 179 DEGs included the genes related to chemokine CC motif ligand, T-cell receptor signaling pathway, and PD-L1 expression and PD-1 checkpoint pathway. We focused on chemokine CC motif ligand, and CCL4 was confirmed to be significantly downregulated in the R-group ( P =0.039). We also focused on the genes related to T-cell signaling pathway, and CD3E ( P =0.039), ITK ( P =0.023), and LAT ( P =0.023) genes were confirmed to be significantly upregulated in the R-group. The current results suggest that both changes in tumor cells and the interactions between tumor cells and immune cells are associated with the efficacy of the chemotherapy for first remission induction.

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“… 13 In this same study, PD-1 was significantly increased on CD8 T cells only (not CD4-positive T cells). Ma et al 17 performed immunohistochemical analysis of 174 DLBCL cases and found that 69.5% and 45.4% showed TIGIT expression on the TILs and lymphoma cells, respectively. This team also found no association between TIGIT expression on lymphoma cells or TILs and survival.…”

Section: Discussionmentioning

confidence: 99%

“…For TIGIT immunohistochemistry, there is no uniform scoring system. Ma et al 17 used a cutoff of 20% positivity in tumor or TILs to categorize each compartment as TIGIT-positive. Others have used graded approaches where <5% to 10% positivity (based on representative images) were used 15 .…”

Section: Methodsmentioning

confidence: 99%

TIGIT is Frequently Expressed in the Tumor Microenvironment of Select Lymphomas

Libert,

Zhao,

Younes

et al. 2023

American Journal of Surgical Pathology

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Immune checkpoint inhibitors against Programmed Cell Death Protein 1/Programmed Cell (PD-1/PD-L1) and CTLA-4/B7 axes have had limited success in hematologic malignancies, requiring the need to explore alternative targets such as T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 to improve durable clinical responses. We undertook this study to investigate the expression profile of TIGIT such that the potential efficacy of TIGIT blockade could be mapped among lymphoma subtypes. We validated an immunohistochemical assay for TIGIT and evaluated its expression in lymphoma and tumor microenvironment (TME) cells in 661 lymphoma/leukemia biopsies. Multiplex immunofluorescence was used for correlation with normal TME cell subsets. Tumor or TME TIGIT-positivity was defined as moderate to strong membrane staining in at least 10% of tumor or TME cells, respectively. TME TIGIT expression was correlated with overall survival and progression-free survival and comparison with PD-L1 expression. In most cases, lymphoma cells were TIGIT-negative except for angioimmunoblastic and peripheral T-cell lymphomas, which showed 91% and 47% positivity, respectively. A high proportion of small B-cell lymphoma and anaplastic large cell lymphoma cases had TIGIT-positive TME cells. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients with TIGIT-negative TME cells showed significantly shorter overall survival (P=0.04). No other statistically significant differences were found. When TIGIT was expressed in TME cells, there were a comparable number of TIGIT-positive only and dual TIGIT/PD-L1 positive cases except for more TIGIT-positive only cases in CLL/SLL. TIGIT expression shows distinctive profiles among lymphoma subtypes. Chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD-L1, with a high proportion of dual TIGIT and PD-L1-positivity. Our results are likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1.

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The immune checkpoint expression in the tumor immune microenvironment of DLBCL: Clinicopathologic features and prognosis

Cited by 8 publications

References 28 publications

Establishment and evaluation of a nomogram for predicting the survival outcomes of patients with diffuse large B-cell lymphoma based on International Prognostic Index scores and clinical indicators

Establishment and evaluation of a nomogram for predicting the survival outcomes of patients with diffuse large B-cell lymphoma based on International Prognostic Index scores and clinical indicators

Gene expression profiles associated with early relapse during first remission induction in canine multicentric high-grade B-cell lymphoma

TIGIT is Frequently Expressed in the Tumor Microenvironment of Select Lymphomas

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