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Background: Aging has long been thought to be a major risk factor for various types of cancers. However, accumulating evidence indicates increased resistance of old animals to tumor growth. An in-depth understanding of how old individuals defend against tumor invasion requires further investigations., Methods: We revealed age-associated alterations in tumor-infiltrating immune cells between young and old mice using single-cell RNA and coupled T cell receptor (TCR) sequencing analysis. Multiple bioinformatics methods were adopted to analyze the characteristics of the transcriptome between two groups. To explore the impacts of young and old CD8 + T cells on tumor growth, mice were treated with anti-CD8 antibody every 3 days starting 7 days after tumor inoculation. Flow cytometry was used to validate the differences indicated by sequencing analysis between young and old mice., Results: We found a higher proportion of cytotoxic CD8 + T cells, naturally occurring Tregs, conventional dendritic cell (DC), and M1-like macrophages in tumors of old mice compared with a higher percentage of exhausted CD8 + T cells, induced Tregs, plasmacytoid DC, and M2-like macrophages in young mice. Importantly, TCR diversity analysis showed that top 10 TCR clones consisted primarily of exhausted CD8 + T cells in young mice whereas top clones were predominantly cytotoxic CD8 + T cells in old mice. Old mice had more CD8 + T cells with a 'progenitor' and less 'terminally' exhausted phenotypes than young mice. Consistently, trajectory inference demonstrated that CD8 + T cells preferentially differentiated into cytotoxic cells in old mice in contrast to exhausted cells in young mice. Importantly, elimination of CD8 + T cells in old mice during tumor growth significantly accelerated tumor development. Moreover, senescent features were demonstrated in exhausted but not cytotoxic CD8 + T cells regardless of young and old mice., Conclusions: Our data revealed that a significantly higher proportion of effector immune cells in old mice defends against tumor progression, providing insights into understanding the altered kinetics of cancer development and the differential response to immunotherapeutic modulation in elderly patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Simple Summary: Immune 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. [ABSTRACT FROM AUTHOR]