Immunosuppressive Microenvironment and Efficacy of PD-1 Inhibitors in Relapsed/Refractory Classic Hodgkin Lymphoma: Checkpoint Molecules Landscape and Macrophage Populations

Gusak, Artem; Fedorova, L.; Lepik, K.; Volkov, Nikita; Popova, M.; Moiseev, Ivan S.; Mikhailova, N.B.; Baykov, Vadim

doi:10.3390/cancers13225676

Cited by 21 publications

(24 citation statements)

References 63 publications

(100 reference statements)

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“…Here, we identified a small subset of CD163 + tissue-resident macrophages that drives both primary and secondary resistance against T cell-targeted immunotherapies in preclinical models. These macrophages were highly comparable to a subset of human macrophages with a functional M2 macrophage signature, 27 that is, enriched in human cancers and shares the expression of Maf in the CD163 + macrophage subset recently associated with low response to checkpoint therapy in patients with leukemia 28 as well as the lack of Csf1r expression in the CD163 + macrophage subset associated with resistance to checkpoint therapy in patients with non-small cell lung cancer. 29 While TAM heterogeneity in function and origin is widely acknowledged, macrophages are often grouped on the basis of a few markers.…”

Section: Discussionmentioning

confidence: 77%

Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy

Elsas

Labrie

Etzerodt

et al. 2023

J Immunother Cancer

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BackgroundPrimary and secondary resistance is a major hurdle in cancer immunotherapy. Therefore, a better understanding of the underlying mechanisms involved in immunotherapy resistance is of pivotal importance to improve therapy outcome.MethodHere, two mouse models with resistance against therapeutic vaccine-induced tumor regression were studied. Exploration of the tumor microenvironment by high dimensional flow cytometry in combination with therapeuticin vivosettings allowed for the identification of immunological factors driving immunotherapy resistance.ResultsComparison of the tumor immune infiltrate during early and late regression revealed a change from tumor-rejecting toward tumor-promoting macrophages. In concert, a rapid exhaustion of tumor-infiltrating T cells was observed. Perturbation studies identified a small but discernible CD163himacrophage population, with high expression of several tumor-promoting macrophage markers and a functional anti-inflammatory transcriptome profile, but not other macrophages, to be responsible. In-depth analyses revealed that they localize at the tumor invasive margins and are more resistant to Csf1r inhibition when compared with other macrophages.In vivostudies validated the activity of heme oxygenase-1 as an underlying mechanism of immunotherapy resistance. The transcriptomic profile of CD163himacrophages is highly similar to a human monocyte/macrophage population, indicating that they represent a target to improve immunotherapy efficacy.ConclusionsIn this study, a small population of CD163hitissue-resident macrophages is identified to be responsible for primary and secondary resistance against T-cell-based immunotherapies. While these CD163hiM2 macrophages are resistant to Csf1r-targeted therapies, in-depth characterization and identification of the underlying mechanisms driving immunotherapy resistance allows the specific targeting of this subset of macrophages, thereby creating new opportunities for therapeutic intervention with the aim to overcome immunotherapy resistance.

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Section: Discussionmentioning

confidence: 77%

Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy

Elsas

Labrie

Etzerodt

et al. 2023

J Immunother Cancer

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“…We have observed up‐regulation of LAG‐3 on CD8 + T cells in 48H 3D‐HyGTIC systems after PD‐1 blockade, which was in line with longitudinal paired tumor tissue analysis from Hodgkin Lymphoma patients. [ 43 ] Recently, using SPECT/CT and radiolabeled LAG‐3, Lecocq et al also reported LAG‐3 upregulation after anti‐PD‐1 treatment in MC38 tumor‐bearing mice. [ 44 ] We further confirmed a LAG‐3 up‐regulation trend on CD8 + T cells in NR group of NSCLC patients at Week 8 when compared to the baseline after nivolumab treatment, whereas no dramatic increase in R patients, suggesting that enhanced expression of LAG‐3 might be a strategy adopted by tumor cells to induce the impairment of CD8 + T cells following PD‐1/PD‐L1 axis blocking, [ 32 ] which was further confirmed in the human 3D‐HyGTIC system as well.…”

Section: Discussionmentioning

confidence: 99%

A 3D Ex Vivo Tumor‐Immune Coculture System Mimicking In Vivo Tumor Environmental Stress on CD8+ T Cells Exhaustion

et al. 2023

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Dissection of exhaustion trajectories of immune cells under tumor selection pressure in the tumor microenvironment (TME) elucidates the underlying machinery in anti‐tumor immunity, which still lacks easy‐to‐use models to decipher. Herein, gelatin methacryloyl (GelMA)–poly (ethylene oxide) (PEO) based 3D hydrogel microspheroids are constructed with non‐immunogenicity and controllable macroporous structure to establish a tumor‐immune cell coculture (3D‐HyGTIC) system. In 3D‐HyGTIC system, when immune cells embarked, stepwise up‐regulation of main immune checkpoints (ICs) molecules is observed with compromised cytokine production in CD8+ T cells, the trajectory of which is in lineage correlation with in vivo grafted tumors. Reinvigoration of CD8+ T cells is more obvious with the addition of an anti‐PD‐1 regimen at the early time point, which is recapitulated during the coculture of patient‐derived tumor fragments (PDTF) and autologous T cells. Moreover, the upregulation of LAG‐3 on CD8+ T cells after anti‐PD‐1 treatment is uncovered. Sequential addition of anti‐LAG‐3 successfully rescues the otherwise failed reactivation of CD8+ T cells. Therefore, the 3D‐HyGTIC system is not only inclined to mimic the early differentiation trajectories of tumor‐infiltrating CD8+ T cells but also may facilitate an evaluation of the efficacy of IC blockades and guide the designing of combination immunotherapy.

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“…c-Maf is essential for macrophage self-renewal but is also expressed in T cells, including Th2 and Th17 cells [27][28][29] . Liu et al identi ed c-Maf as an essential regulator for immunosuppressive macrophage polarization 27 and showed that c-Maf is predominantly expressed in M2-like macrophages in both mice and humans 27 .…”

Section: Discussionmentioning

confidence: 99%

“…In this study, PD-L1 expression in cancer cells and surrounding immune cells was not correlated with survival in patients with LAD, suggesting that PD-L1 expression cannot predict outcomes in these patients. Although cancer immunotherapy using anti-PD-L1 immunocheckpoint inhibitors has been widely applied in patients with non-small cell lung cancer, many patients are resistant to such treatment [29][30][31][32][33] . Inhibition of c-Maf may contribute to overcoming such resistance 27 .…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of tumor-associated macrophage-related markers in patients with adenocarcinoma of the lung

Shikanai

Yamada

Yanagawa

et al. 2022

Preprint

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Macrophage polarization is an important pathogenetic factor in neoplastic diseases and is regulated by transcription factors, i.e., phosphorylated signal transducer and activator of transcription 1 (phospho-STAT1) for the M1 phenotype and c-Maf for the M2 phenotype. However, the role of macrophage phenotype in lung adenocarcinoma (LAD) remains unclear. Here, we examined whether the density of M1 and M2 macrophages was associated with prognosis in patients with LAD using double-labeling immunohistochemistry for the detection of macrophage markers. Additionally, programmed death ligand 1 (PD-L1) expression was investigated. Immune cells co-expressing CD68 and phospho-STAT1 were considered M1 macrophages, whereas those co-expressing CD68 and c-Maf were recognized as M2 macrophages. Three hundred seven patients with LAD were divided into two cohorts (N = 100 and 207 cases, respectively) to evaluate the associations of M1 and M2 phenotypes with prognosis in patients with LAD. We determined the cut-off values of CD68/phospho-STAT1-positive cells (5 or less) and CD68/c-Maf-positive cells (more than 11) to assess correlations with survival using receiver operating characteristic curve analysis in the first cohort. According to the cut-off values, high expression of CD68/c-Maf was identified as an independent prognostic marker, whereas CD68/Phospho-STAT1 expression was inversely correlated with patient outcomes. Moreover, the M1/M2 ratio (0.19 or less) was a poor prognostic factor for LAD. However, PD-L1 expression was not correlated with patient outcomes. Overall, these findings suggested that double staining of markers identifying M1 and M2 macrophages, including phospho-STAT1 and c-Maf, can be used as prognostic indicators for patients with LAD.

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Immunosuppressive Microenvironment and Efficacy of PD-1 Inhibitors in Relapsed/Refractory Classic Hodgkin Lymphoma: Checkpoint Molecules Landscape and Macrophage Populations

Cited by 21 publications

References 63 publications

Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy

Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy

A 3D Ex Vivo Tumor‐Immune Coculture System Mimicking In Vivo Tumor Environmental Stress on CD8+ T Cells Exhaustion

Prognostic impact of tumor-associated macrophage-related markers in patients with adenocarcinoma of the lung

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