bims-myxlip 2023-02-19 papers

Issue of 2023–02–19
two papers selected by
Laura Mannarino, Humanitas Research

Acta Oncol. 2023 Jan;62(1): 33-39

Immune-cell infiltration in high-grade soft tissue sarcomas; prognostic implications of tumor-associated macrophages and B-cells.

Helena Nyström, Mats Jönsson, Mef Nilbert, Ana Carneiro.

BACKGROUND: Soft tissue sarcomas are rare, morphologically, and genetically heterogenous. Though the tumors display abundant tumor stroma with infiltrating immune cells, the prognostic impact of various immunologic markers in sarcoma remains poorly defined. We aimed to characterize the immune landscape of a treatment-naïve cohort of soft tissue sarcoma of the extremities and the trunk wall with correlations to metastasis-free survival.
MATERIALS AND METHODS: We surveyed immunohistochemical expression patterns for CD163, CD20, CD3, CD8, and FOXP3 in 134 adult high-grade leiomyosarcomas, liposarcomas, and synovial sarcomas.
RESULTS: Macrophages outnumbered tumor-infiltrating lymphocytes. High CD163 infiltration was identified in 49% of the tumors and was overrepresented (66%) in leiomyosarcoma compared to liposarcoma (46%) and synovial sarcoma (9%). Tumor-grade also correlated with CD163 positivity with high expression in 53% of the high-grade lesions and 28% in low-grade tumors. Infiltrating CD3, CD8 and FOXP3-positive T-cells were significantly more prevalent in leiomyosarcomas than in liposarcomas/synovial sarcomas. CD20+ B-cells were identified only in 14% of the STS. Correlation to established prognostic factors revealed a correlation between CD163+ macrophages and necrosis and predicted an increased risk of metastases. No correlation between CD20+ B-cells and known prognostic factors could be established, though CD20+ B-cells infiltration predicted improved overall survival.
CONCLUSION: We confirm that tumor-infiltrating macrophages outnumber tumor-infiltrating lymphocytes in soft tissue sarcoma and signify an increased risk of metastasis. CD20+ B-cells are scarce in STS and correlate to improved survival. To date, immunotherapeutic strategies directed against T-cells have shown limited effect in soft tissue sarcoma. Our observations suggest that immunomodulatory agents focusing on macrophages may be worthwhile for further investigations in this tumor type. Further studies exploring the prognostic and predictive significance of CD20+ B cells are warranted.

Keywords: cd163; cd20; sts; tam; tme

DOI: https://doi.org/10.1080/0284186X.2023.2172688

EMBO Mol Med. 2023 Feb 13. e16863

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma.

Lara Planas-Paz, Alicia Pliego-Mendieta, Catherine Hagedorn, Domingo Aguilera-Garcia, Martina Haberecker, Fabian Arnold, Marius Herzog, Lorenz Bankel, Roman Guggenberger, Sabrina Steiner, Yanjiang Chen, Abdullah Kahraman, Martin Zoche, Mark A Rubin, Holger Moch, Christian Britschgi, Chantal Pauli.

Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.

Keywords: HRD score; HRDness; genomic instability; sarcoma

DOI: https://doi.org/10.15252/emmm.202216863