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The immune suppressive microenvironment affects efficacy of radio-immunotherapy in brain metastasis.

ABSTRACT: The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T-cell-directed therapies fail to elicit effective anti-tumor immune responses. Here, we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T-cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastasis. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1⁺ myeloid cells after radio-immunotherapy indicating the establishment of an immune suppressive environment to counteract re-activated T-cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune suppression and regulating T-cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.

SUBMITTER: Niesel K

PROVIDER: S-EPMC8103101 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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The immune suppressive microenvironment affects efficacy of radio-immunotherapy in brain metastasis.

Niesel Katja K Schulz Michael M Anthes Julian J Alekseeva Tijna T Macas Jadranka J Salamero-Boix Anna A Möckl Aylin A Oberwahrenbrock Timm T Lolies Marco M Stein Stefan S Plate Karl H KH Reiss Yvonne Y Rödel Franz F Sevenich Lisa L

EMBO molecular medicine 20210323 5

The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T-cell-directed therapies fail to elicit effective anti-tumor immune responses. Here, we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radioth ...[more]

PMID: 33755340

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Project description:ObjectiveLaminin subunit Beta-1 (LAMB1), a component of the extracellular matrix, has been reported to be implicated in the development and progression of cancer. However, the role of LAMB1 in Nasopharyngeal Carcinoma (NPC) remains unknown.MethodsThree NPC datasets were utilized to identify LAMB1 as a targeted gene. The correlation between LAMB1 expression and clinical characteristics, prognosis was explored. KEGG and GO enrichment analyses were conducted to investigate LAMB1's functions in NPC. The CIBERSORT, xCell, MCPCOUNTER, and EPIC methods were used to assess the Cancer-Associated Fibroblasts (CAFs) and immune cells infiltration. We predicted LAMB1's effect on treatment using TIDE, CTRP, and CellMine databases. Finally, Western blot, CCK-8, Transwell, and Wound scratch were employed to validate LAMB1's effect on NPC cells.ResultsLAMB1 was highly expressed in NPC. High-expression LAMB1 was correlated with poorer progression-free survival and impeded the infiltration of CD4+ T-cells, CD8+ T-cells and dendritic cells. It also diminished the expression of HLA and suppressed T-cells stimulation. Differential expressed cytokines and involved pathways were divergent across different level of fibroblasts infiltration. At high level of fibroblasts, LAMB1 indirectly inhibited immune cells by remolding extracellular matrix. But at low level of fibroblasts, LAMB1 directly suppressed immune response. Tumors with high LAMB1 level had weak responses to immunotherapy. In vitro experiment, LAMB1 significantly suppressed HLA-1 and enhanced the proliferation, migration, and invasion capabilities of NPC cells.ConclusionHigh expression of LAMB1 is significantly associated with an immune-suppressive tumor microenvironment in NPC. LAMB1 enhances the proliferation, migration and invasion of NPC cells. These findings suggest that LAMB1 may serve as a prognostic biomarker for predicting NPC progression and a potential therapeutic target to enhance the efficacy of existing immunotherapies.Level of evidence: 3

Project description:BackgroundThe current exploration of the tumor immune microenvironment is enthusiastic, but few studies explored the impact of angiogenesis on the immune microenvironment. Immunotherapy combined with anti-angiogenesis therapy has become one of the first-line treatment for lung adenocarcinoma. Our study aimed to explore the reasons for resistance of immunotherapy, and explore markers for immunotherapy combined with anti-angiogenesis therapy.MethodsFirst, by unsupervised clustering of 36 angiogenesis-related genes in lung adenocarcinoma patients from TCGA database, AGS1 and AGS2 groups were distinguished with significantly different clinical outcomes. Secondly, the immune microenvironment and metabolic characteristics were analyzed. Next, we used the GDSC and GEO database to analyze therapeutic responses. Then, through multivariate Cox regression, the hub gene: JAG1, significantly related to prognosis was selected, and further verified by multi-omics data. Finally, we validated that patient with high JAG1 expression had a low immune-infiltrating tumor microenvironment through single-cell transcriptomic data.ResultsCompared with the AGS1 group, AGS2 showed an immune "cold" phenotype with lower lymphocyte infiltration, and was associated with worse prognoses. At the same time, the immunosuppressive TGF-β response was significantly higher in AGS2. Furthermore, the glycolysis ability of the AGS2 was stronger than AGS1. The expression of JAG1 was significantly higher in the AGS2, and was significantly negatively correlated with the degree of immune infiltration, accompanying with higher glycolytic capacity. The above results indicate that patients with high expression of JAG1 may lead to immunosuppressive phenotype due to its strong glycolytic capacity, thus making immunotherapy resistance.ConclusionPatients with high expression of JAG1 enhanced glycolytic capacity was likely to cause suppressed immune microenvironment. JAG1 may be a marker for resistance of immunotherapy. Combining anti-angiogenesis therapy could be considered to improve the prognosis of those patients.

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The immune suppressive microenvironment affects efficacy of radio-immunotherapy in brain metastasis.

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The immune suppressive microenvironment affects efficacy of radio-immunotherapy in brain metastasis.

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