Abstract
Simple SummaryImmune cells can be powerful regulators of tumor growth and disease progression. Yet, the potential role of professional antigen-presenting cells in soft tissue sarcoma is poorly explored. Both dendritic cells and macrophages may present exogenous antigens through major histocompatibility complex (MHC) class I molecules to CD8+ T cells, a process referred to as cross presentation. With the concept of cellular cross presentation in mind, the present study supports the hypothesis that CD11c+ cells in direct cell-cell contact with CD8+ T cells within the primary tumor are associated with an active anti-tumor immune microenvironment and favorable prognosis. Our work hereby defines a novel biomarker for immune surveillance where presence of spatial cross presentation at tissue level resolution is significantly associated with overall survival. Importantly, this biomarker is independent from established prognostic markers like tumor grade. Biomarkers linked to immune surveillance are expected to gain increasing attention with the advent of immunotherapy in clinical practice.Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.
Highlights
Soft tissue sarcoma (STS) is a rare, heterogeneous group of extraosseous connective tissue malignancies of embryonic mesodermal origin
Presence of direct cell–cell interactions between CD11c+ cells and CD8+ cells correlated with superior Metastasis-free survival (MFS) and Overall survival (OS) (Figure 1b)
Double immunofluorescence confirmed that CD11c and CD8 were typically not expressed by the same cell population (Figure 1c)
Summary
Soft tissue sarcoma (STS) is a rare, heterogeneous group of extraosseous connective tissue malignancies of embryonic mesodermal origin. Mortality rates are typically high, but the five-year overall survival depends on many tumor- and host-related factors [1,2]. During the last 20 years, numerous molecular biomarkers have been explored in STS [7,8]. These include pan-cancer proliferation markers, such as Ki-67, and sarcomaspecific fusion genes. Some of these markers are today used in the diagnostic or responsepredictive setting. Imatinib is used to successfully inhibit abnormal kinase signaling in c-kit-mutated gastrointestinal stromal tumors [11]
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