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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 |

REPOSITORIES: biostudies-literature

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

Project description: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.

| S-SCDT-EMM-2020-13412 | biostudies-other

The immune suppressive tumor microenvironment affects efficacy of radio-immunotherapy in breast-to-brain metastasis

Project description:The tumor microenvironment in brain metastases is characterized by high myeloid cell content 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 metastases. 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.

2021-02-12 | GSE164049 | GEO

The immune suppressive tumor microenvironment affects efficacy of radio-immunotherapy in breast-to-brain metastasis

Project description:The immune suppressive tumor microenvironment affects efficacy of radio-immunotherapy in breast-to-brain metastasis

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Evolution of the Tumor Microenvironment toward Immune-Suppressive Seclusion during Brain Metastasis of Breast Cancer: Implications for Targeted Therapy.

Project description:Breast cancer (BC) is the second most common solid malignant tumor that metastasizes to the brain. Despite emerging therapies such as immunotherapy, whether the tumor microenvironment (TME) in breast cancer brain metastasis (BCBM) has potential as a target of new treatments is unclear. Expression profiling of 770 genes in 12 pairs of primary BC and matched brain metastasis (BM) samples was performed using the NanoString nCounter PanCancer IO360TM Panel. Immune cell profiles were validated by immunohistochemistry (IHC) in samples from 50 patients with BCBM. Pathway analysis revealed that immune-related pathways were downregulated. Immune cell profiling showed that CD8+ T cells and M1 macrophages were significantly decreased, and M2 macrophages were significantly increased, in BM compared to primary BC samples (p = 0.001, p = 0.021 and p = 0.007, respectively). CCL19 and CCL21, the top differentially expressed genes, were decreased significantly in BM compared to primary BC (p < 0.001, both). IHC showed that the CD8+ count was significantly lower (p = 0.027), and the CD163+ and CD206+ counts were higher, in BM than primary BC (p < 0.001, both). A low CD8+ T cell count, low CD86+ M1 macrophage count, and high M2/M1 macrophage ratio were related to unfavorable clinical outcomes. BC exhibits an immunosuppressive characteristic after metastasis to the brain. These findings will facilitate establishment of a treatment strategy for BCBM based on the TME of metastatic cancer.

| S-EPMC8507988 | biostudies-literature

The suppressive tumor microenvironment: a challenge in cancer immunotherapy.

Project description:In this review, we introduce the changing public perception of vaccines and immunotherapy in cancer treatments. We discuss the roles that different immunosuppressive cells play in the tumor microenvironment. Tumor associated macrophages (TAMs) and M1 and M2 macrophage phenotypes are discussed in depth. Additionally, the role that myeloid derived suppressor cells (MDSC) and T regulatory cells (Tregs) play in the tumor microenvironment is addressed. Highlighted are examples of therapies used against each suppressive cell type, which vary from the hypothetical to the ineffective; the inefficient to the successful. A variety of treatments have been tried to combat this fundamental problem, indeed the cause that allows cancerous mutated cells to survive, multiply and overtake the body. Efficient methods to disable each particular suppressive type of cell have been introduced; this review summarizes the discussion with a table to guide future development. We see gene therapy as the most innovative and flexible method to lead the charge to specifically modifying the tumor microenvironment.

| S-EPMC5514373 | biostudies-literature

Immune microenvironment remodeling after radiation of a progressing brain metastasis.

Project description:Radiation is commonly used in the treatment of many cancers. However, its effects on anti-tumor immune responses are incompletely understood. Here, we present a detailed immunological analysis of two tumors from a patient with multiple non-small cell lung cancer metastases to the brain. One tumor was resected without treatment; the second was irradiated to a total dose of 30 Gy and resected following further progression. Comprehensive single-cell analysis reveals a substantially reduced immune cell fraction in the irradiated tumor, including the depletion of tissue-resident macrophages and infiltration of pro-inflammatory monocytes. Despite the presence of similar somatic mutations in both tumors, radiation is associated with the depletion of exhausted, tumor-resident T cell clones and their replacement by circulating clones unlikely to contribute to tumor-specific immunity. These results provide insight into the local effects of radiation on anti-tumor immunity and raise important considerations for the combination of radiation and immunotherapy.

| S-EPMC10313918 | biostudies-literature

Inhibiting Notch1 enhances immunotherapy efficacy in melanoma by preventing Notch1 dependent immune suppressive properties.

Project description:We have previously shown that Notch1 plays a critical role in modulating melanoma tumor cell growth and survival. Here we show that Notch1 also contributes to an immune-suppressive tumor microenvironment (TME). Notch1 inhibition reduces immune suppressive cells (i.e. MDSCs and Tregs) while allowing the recruitment of functional CD8(+) T cells, leading to a decrease in the Tregs/CD8(+) ratio, a key parameter in assessing positive responses to immune-checkpoint inhibitors. Inhibition of Notch1 improves the antitumor activity of nivolumab and ipilimumab, particularly when given in combination. Mechanistically, tumor-associated Notch1 regulates the expression of several chemokines involved in MDSCs and Tregs recruitment. Among them, CCL5, IL6 and IL8, or MIP2 in mouse, were consistently reduced by Notch1 depletion in several human and mouse melanoma cell lines. Notch1 controls the transcription of IL8 and IL6; and the secretion of CCL5 likely by inhibiting the expression of SNAP23, a member of the SNAREs family of proteins involved in cell exocytosis. Inhibition of SNAP23 decreases CCL5 secretion similarly to Notch1 inhibition. Hence, targeting Notch1 would affect both melanoma intrinsic growth/survival properties, and provide an immune-responsive TME, thus improving immune therapy efficacy.

| S-EPMC7185871 | biostudies-literature

Immune suppressive microenvironment in brain metastatic non-small cell lung cancer: comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060).

Project description:Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1/high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.

| S-EPMC8986255 | biostudies-literature

Tumor immune microenvironment and immunotherapy efficacy in BRAF mutation non-small-cell lung cancer.

Project description:Previous small-size studies reported BRAF-mutated NSCLC patients have comparable sensitivity to immune checkpoint inhibitors (ICIs). However, how BRAF mutation affects the tumor immune microenvironment (TIME) is unknown. We performed Nanostring-panel RNA sequencing to evaluate TIME in 57 BRAF mutated and wild-type (WT) NSCLC specimens (cohort A). The efficacy of ICI monotherapy or combined therapies was determined in 417 patients with WT and BRAF mutated NSCLC (cohort B). We found that BRAF-mutant tumors had similar ratios of CD8+ T cells to Tregs, the balance of cytotoxicity gene expression signatures and immune suppressive features, and similar ICI-response-related biomarkers to WT NSCLC. A similar TIME pattern was observed between the BRAF V600E and Non-V600E subgroups of NSCLC. The further retrospective study confirmed that treatment with ICI monotherapy or combined therapies resulted in similar overall survival (OS) (HR: 0.85; 95% CI, 0.56 to 1.30; p = 0.47) and progress-free survival (PFS) (HR: 1.02; 95% CI, 0.72 to 1.44; p = 0.91) of patients with WT (n = 358) and BRAF mutant (n = 59) NSCLC. Similarly, both patients with BRAF V600E or Non-V600E NSCLC had similar responses to immunotherapy. Our findings support that BRAF mutation did not modulate TIME in NSCLC and therapeutic responses to ICIs. Patients with NSCLC harboring BRAF mutation should not be denied treatment with ICIs.

| S-EPMC9772302 | biostudies-literature

Immunotherapy: Reshape the Tumor Immune Microenvironment.

Project description:Tumor immune microenvironment (TIME) include tumor cells, immune cells, cytokines, etc. The interactions between these components, which are divided into anti-tumor and pro-tumor, determine the trend of anti-tumor immunity. Although the immune system can eliminate tumor through the cancer-immune cycle, tumors appear to eventually evade from immune surveillance by shaping an immunosuppressive microenvironment. Immunotherapy reshapes the TIME and restores the tumor killing ability of anti-tumor immune cells. Herein, we review the function of immune cells within the TIME and discuss the contribution of current mainstream immunotherapeutic approaches to remolding the TIME. Changes in the immune microenvironment in different forms under the intervention of immunotherapy can shed light on better combination treatment strategies.

| S-EPMC9299092 | biostudies-literature

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