Oncogenic drivers dictate immune control of acute myeloid leukemia

Austin, Rebecca; Straube, Jasmin; Halder, Rohit; Janardhanan, Yashaswini; Bruedigam, Claudia; Witkowski, Matthew T; Cooper, Leanne; Porter, Amy H.; Braun, Matthias; Souza-Fonseca-Guimarães, Fernando; Minnie, Simone A.; Cooper, Emily; Jacquelin, Sébastien; Song, Axia; Bald, Tobias; Nakamura, Kyohei; Hill, Geoffrey R.; Aifantis, Iannis; Lane, Steven; Bywater, Megan J.

doi:10.1038/s41467-023-37592-9

Cited by 9 publications

(5 citation statements)

References 62 publications

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“…Although we did not investigate the direct consequences of these molecular alterations, such as alterations in the expression of immunomodulatory surface molecules 38,39 , we identified M2-like macrophage predominance in immune-depleted cases. The observed negative correlation between the M2-:M1-like macrophage ratio and the extent of T cell infiltration is consistent with data from (preclinical) studies in other cancers, suggesting a role for M2-like macrophages (or a lack of M1-like macrophages) in limiting T cell infiltration to the leukemic BM 40,41 .…”

Section: Discussionmentioning

confidence: 79%

“…S1A-D). These results indicate that other variables such as AML molecular aberrations (e.g., mutated NPM1 and WT-1) may be more relevant in shaping BM T cell infiltration 16 . However, AML molecular aberrations were not reported in the majority of cases (78%), which precluded meaningful analyses.…”

Section: A Subset Of Pediatric Aml Patients Has High T Cell Infiltrat...mentioning

confidence: 84%

“…Taken together, we identified wide heterogeneity in T cell infiltration in the BM of pediatric AML with nearly one-third of cases (31%) showing notably high T cell infiltration. In addition, our findings suggest that specific genetic alterations may be linked to the extent of T cell infiltration in the BM of pediatric AML, although the exact underlying mechanisms remain to be unraveled 38,39 .…”

Section: A Subset Of Pediatric Aml Patients Has High T Cell Infiltrat...mentioning

confidence: 89%

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A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia

Koedijk

Werf

Vermeulen

et al. 2023

Preprint

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Pediatric cancers are characterized by a relatively low mutational burden and therefore, children are thought to be poor candidates for T cell-engaging immunotherapies. Here, we performed a multidimensional characterization of the tumor immune microenvironment in newly diagnosed children with acute myeloid leukemia (AML) and non-leukemic controls. We identified a subset of pediatric AML patients with remarkably high levels of T cell infiltration and a relatively low abundance of anti-inflammatory macrophages. In addition, we detected large T cell networks that colocalized with B cells in the bone marrow of immune-infiltrated samples, resembling tertiary lymphoid structures as described in solid tumors. Using spatial transcriptomics, we dissected the composition of these structures and revealed unique hotspots of anti-tumor immunity. This work raises the possibility that a subset of pediatric AML patients may benefit from T cell-engaging immunotherapies and encourages further study of these lymphoid structures in the context of immunotherapy in AML.Disclosure of conflicts of interestThe authors declare no financial conflicts of interest.

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Section: Discussionmentioning

confidence: 79%

Section: A Subset Of Pediatric Aml Patients Has High T Cell Infiltrat...mentioning

confidence: 84%

Section: A Subset Of Pediatric Aml Patients Has High T Cell Infiltrat...mentioning

confidence: 89%

See 1 more Smart Citation

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia

Koedijk

Werf

Vermeulen

et al. 2023

Preprint

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“…Moreover, the estimated abundance of several immunosuppressive cell subsets (M2-/M1-like macrophage ratio, cancer-associated fibroblasts, and myeloid-derived suppressor cells) was increased at AML diagnosis, suggesting that the BM microenvironment had become more immunosuppressive over time ( Figures 2G–I ) ( 14 ). Consequently, we speculate that the additional genetic alterations identified at AML diagnosis led to immune escape of the (pre)leukemic clone ( 9 , 22 ).…”

Section: Resultsmentioning

confidence: 98%

Case Report: Immune dysregulation associated with long-lasting regression of a (pre)leukemic clone

Koedijk,

van Beek,

Vermeulen

et al. 2023

Front. Immunol.

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Regression of leukemia in the absence of disease-modifying therapy remains poorly understood, although immunological mechanisms are thought to play a role. Here, we present a unique case of a 17-year-old boy with immune dysregulation and long-lasting regression of a (pre)leukemic clone in the absence of disease-modifying therapy. Using molecular and immunological analyses, we identified bone marrow features associated with disease control and loss thereof. In addition, our case reveals that detection of certain fusion genes with hardly any blasts in the bone marrow may be indicative of an accompanying oncogenic fusion gene, with implications for disease surveillance- and management in future patients.

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“…Various evidence recently showed how distinct molecular features, such as NPM1 and FLT3 mutations, differently modulate immune responses in AML, both in terms of immune response quality and immune escape [ 64 , 65 , 66 ].…”

Section: Immune Landscape In Amlmentioning

confidence: 99%

Checkpoint Inhibitors in Acute Myeloid Leukemia

Damiani

Tiribelli

2023

Biomedicines

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The prognosis of acute myeloid leukemia (AML) remains unsatisfactory. Among the reasons for the poor response to therapy and high incidence of relapse, there is tumor cell immune escape, as AML blasts can negatively influence various components of the immune system, mostly weakening T-cells. Since leukemic cells can dysregulate immune checkpoints (ICs), receptor-based signal transductors that lead to the negative regulation of T-cells and, eventually, to immune surveillance escape, the inhibition of ICs is a promising therapeutic strategy and has led to the development of so-called immune checkpoint inhibitors (ICIs). ICIs, in combination with conventional chemotherapy, hypomethylating agents or targeted therapies, are being increasingly tested in cases of AML, but the results reported are often conflicting. Here, we review the main issues concerning the immune system in AML, the main pathways leading to immune escape and the results obtained from clinical trials of ICIs, alone or in combination, in newly diagnosed or relapsed/refractory AML.

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Oncogenic drivers dictate immune control of acute myeloid leukemia

Cited by 9 publications

References 62 publications

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia

Case Report: Immune dysregulation associated with long-lasting regression of a (pre)leukemic clone

Checkpoint Inhibitors in Acute Myeloid Leukemia

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