Understanding the immune responses in angiosarcomas and their clinical implications
Angiosarcomas are clinically-aggressive cancers that are more prevalent in Asian populations. Recent studies demonstrated distinct subtypes defined by unique molecular and immune profiles. In this work, we investigated the immune responses in angiosarcomas and examined their clinical implications.
Rare cancers collectively account for 25% of all malignancies, and contrary to popular belief, represent a major healthcare problem worldwide. Recent efforts have been made to unravel the genomic landscape of sarcoma – the prototypical rare cancer that represents only 1% of all cancer types, but with over 100 subtypes, each with its own unique clinical course, molecular profile, and treatment challenges.
Some of our recent work at the National Cancer Centre Singapore has been focused on understanding the clinical and molecular features of soft tissue sarcoma. Earlier, we had shown that the systemic immune response to the development of sarcoma varies according to their biological phenotype and clinical behaviour. Specifically, we found that a high baseline peripheral blood neutrophil-to-lymphocyte ratio (NLR) was associated with adverse biological features such as distant metastasis at diagnosis, higher tumour grade, larger tumour size, as well as greater tumour depth. A high ratio was associated with worse overall survival and relapse-free survival across various sarcoma subtypes . Interestingly, this peripheral immune response may potentially be a predictive biomarker to checkpoint immunotherapy – an emerging modality in sarcoma therapeutics . Extending these findings, we subsequently dived into a detailed investigation into the genomic and immune profiles of angiosarcoma, an Asian-centric rare cancer, uncovering distinct mutational signatures and gene expression profiles, as well as immune signatures in this disease [3, 4].
Given this background, we were interested in studying the systemic as well as intra-tumoral immune responses, and how these may relate to disease biology and actual patient outcomes. To that end, we studied a total of 150 patients with histologically-proven angiosarcoma seen at our centre over the past 20 years, and correlated their clinical features with the NLR as a marker of systemic immune response, as well as the association with intra-tumoral immune profiles using the NanoString PanCancer IO360 panel and multiplex immunohistochemistry. Interestingly, we found that the systemic and intra-tumoural immune responses were not only closely intertwined, they were associated with the activation of oncogenic pathways including angiogenesis, matrix remodeling and metastasis, and cytokine and chemokine signaling. Importantly, high levels of activity in these immune-oncogenic signals were associated with primary resistance to chemotherapy, thereby leading to worse survival .
Where do we go from here? Moving forwards (excitedly!), we are embarking on a new initiative called “STARLIGHT”, which aims to comprehensively investigate the molecular and immune pathobiology of rare cancers, with particular interest in profiling their clinically-actionable target landscape for precision therapy. By putting “Sarcoma and Rare Cancers in the Light”, we hope to increase the molecular understanding of rare cancers and eventually improve clinical outcomes of this group of diseases with unmet clinical need.
- Chan JY, Zhang Z, Chew W, Tan GF, Lim CL, Zhou L, et al. Biological significance and prognostic relevance of peripheral blood neutrophil-to-lymphocyte ratio in soft tissue sarcoma. Sci Rep. 2018;8:11959. doi: 10.1038/s41598-018-30442-5.
- Wilky BA, Trucco MM, Subhawong TK, Florou V, Park W, Kwon D, et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol. 2019;20:837-848. doi: 10.1016/S1470-2045(19)30153-6.
- Chan JY, Lim JQ, Yeong J, Ravi V, Guan P, Boot A, et al. Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma. J Clin Invest. 2020;130:5833-5846. doi: 10.1172/JCI139080.
- Tan GF, Goh S, Lim AH, Liu W, Lee JY, Rajasegaran V, et al. Bizarre giant cells in human angiosarcoma exhibit chemoresistance and contribute to poor survival outcomes. Cancer Sci. 2021;112:397-409. doi: 10.1111/cas.14726.
- Chan JY, Tan GF, Yeong J, Ong CW, Ng DYX, Lee E, et al. Clinical implications of systemic and local immune responses in human angiosarcoma. NPJ Precis Oncol. 2021;5:11. doi: 10.1038/s41698-021-00150-x.