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Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies.

ABSTRACT: Background: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163+ macrophages, CD3+ T-cells, PD-L1/PD-L2 and HLA class I expression (HCA2, HC10 and ?2m) were evaluated using immunohistochemistry in primary tumors (n = 75), local relapses (n = 6) and metastases (n = 19) of 87 LMS patients, as well as in benign leiomyomas (n = 7). Correlation with clinicopathological parameters and survival analyses were assessed. Effect of LMS cells on macrophage differentiation was investigated using coculture of CD14+ monocytes with LMS cell lines or their conditioned media (CM). Results: 58% and 52% of the tumors were highly infiltrated with CD163+ macrophages and T-cells, respectively, with HLA class I expression observed in almost all tumors and PD-L1 expression in 30%. PD-L2 expression was also detected in some PD-L1+ tumors. All these immune markers correlated with high tumor grade but only CD163 associated with overall survival (p = 0.003) and disease-specific survival (p = 0.041). In vitro, CD163 was upregulated in the presence of LMS cells producing M-CSF, suggesting that this tumor drives macrophages towards the M2 phenotype. Conclusion: The clinical significance of M2 macrophages, possibly induced by LMS cell-secreted factors, suggests that 2/3 of high-grade LMS patients might benefit from macrophage-targeting agents. Furthermore, PD-L1 expression together with high T-cell infiltrate and HLA class I expression in around 30% of high grade LMS reflects an active immune microenvironment potentially responsive to immune checkpoint inhibitors.

SUBMITTER: Kostine M

PROVIDER: S-EPMC5749622 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies.

Kostine Marie M Briaire-de Bruijn Inge H IH Cleven Arjen H G AHG Vervat Carly C Corver Willem E WE Schilham Marco W MW Van Beelen Els E van Boven Hester H Haas Rick L RL Italiano Antoine A Cleton-Jansen Anne-Marie AM Bovée Judith V M G JVMG

Oncoimmunology 20171026 2

Background: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163+ macrophages, CD3+ T-cells, PD-L1/PD-L2 and HLA class I expression (HCA2, HC10 and β2m) were evaluated using immunohistochemistry in primary tumors (n = 75), local relapses (n = 6) and metastases ...[more]

PMID: 29308311

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Project description:BackgroundMany clinical studies have shown that patients with non-small cell lung carcinoma (NSCLC) can benefit from immune checkpoint inhibitor (ICI) therapy; however, PD-L1 and tumor mutation burden (TMB), which are recommended by the NCCN guidelines, are still insufficient in predicting the response to and prognosis of immunotherapy. Given the widespread use of ICIs, it is important to find biomarkers that can predict immunotherapy outcomes in NSCLC patients, and the exploration of additional effective biomarkers for ICI therapy is urgently needed.MethodsA total of 33 stage II-IV NSCLC patients were included in this study. We analyzed immune markers in biopsy and surgical tissue resected from these patients before treatment with ICIs. We examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD68/CD163/PD-L1 antibodies.ResultsIn this cohort, we observed that the levels of CD8+ T cells, CD8+PD-L1+ T cells, and CD68+CD163+ M2 macrophages in the total region were independent prognostic factors for progression-free survival (PFS) in NSCLC patients treated with ICIs (HR=0.04, P=0.013; HR=17.70, P=0.026; and HR=17.88, P=0.011, respectively). High infiltration of CD8+ T cells and low infiltration of CD8+PD-L1+ T cells throughout the region were correlated with prolonged PFS (P=0.016 and P=0.02, respectively). No statistically significant difference was observed for CD68+CD163+ M2 macrophages. The joint parameters CD8+ high/CD8+PD-L1+ low, CD8+ high/CD68+CD163+ low and CD8+PD-L1+ low/CD68+CD163+ low predicted better PFS than other joint parameters (P<0.01, P<0.01, and P<0.001, respectively), and they also demonstrated stronger stratification than single biomarkers. The response rate of patients with high infiltration of CD8+ T cells was significantly higher than that of those with low infiltration (P<0.01), and the joint parameters CD8+/CD8+PD-L1+ and CD8+/CD68+CD163+ also demonstrated stronger stratification than single biomarkers.ConclusionsThis retrospective study identified the predictive value of CD8+PD-L1+ T cells, CD8+ T cells, and CD68+CD163+ M2 macrophages in NSCLC patients who received ICIs. Interestingly, our results indicate that the evaluation of joint parameters has certain significance in guiding ICI treatment in NSCLC patients.

Dataset Information

Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies.

Publications

Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies.

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