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Volume 13
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10.3390/cancers13051175
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Article

CD11c-CD8 Spatial Cross Presentation: A Novel Approach to Link Immune Surveillance and Patient Survival in Soft Tissue Sarcoma

by
Yanhong Su
1,
Panagiotis Tsagkozis
2,
Andri Papakonstantinou
1,3,
Nicholas P. Tobin
1,
Okan Gultekin
4,
Anna Malmerfelt
1,
Katrine Ingelshed
4,
Shi Yong Neo
1,
Johanna Lundquist
1,
Wiem Chaabane
1,
Maya H. Nisancioglu
1,
Lina W. Leiss
1,
Arne Östman
1,5,
Jonas Bergh
1,3,
Saikiran Sedimbi
4,
Kaisa Lehti
4,6,
Andreas Lundqvist
1,
Christina L. Stragliotto
3,
Felix Haglund
1,7 and
Monika Ehnman
1,*
1
Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Visionsgatan 4, 171 64 Solna, Sweden
2
Department of Molecular Medicine and Surgery, Karolinska Institutet and Muskuloskeletal Tumor Service, Karolinska University Hospital, 171 76 Stockholm, Sweden
3
Department of Breast Cancer, Endocrine Tumors and Sarcoma, Karolinska University Hospital, 171 76 Stockholm, Sweden
4
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65 Solna, Sweden
5
Centre for Cancer Biomarkers CCBIO, University of Bergen, 5021 Bergen, Norway
6
Department of Biomedical Laboratory Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway
7
Department of Clinical Pathology and Cytology, Karolinska University Hospital, 171 76 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
Academic Editor: Tomoki Nakamura
Cancers 2021, 13(5), 1175; https://doi.org/10.3390/cancers13051175
Received: 23 January 2021 / Revised: 1 March 2021 / Accepted: 5 March 2021 / Published: 9 March 2021
(This article belongs to the Special Issue Sarcomas: New Biomarkers and Therapeutic Strategies)
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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.

Abstract

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. View Full-Text
Keywords: soft tissue sarcoma; UPS; liposarcoma; tumor microenvironment; immune cells; CD11c; CD8; cross presentation; antigen-presenting cells soft tissue sarcoma; UPS; liposarcoma; tumor microenvironment; immune cells; CD11c; CD8; cross presentation; antigen-presenting cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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MDPI and ACS Style

Su, Y.; Tsagkozis, P.; Papakonstantinou, A.; Tobin, N.P.; Gultekin, O.; Malmerfelt, A.; Ingelshed, K.; Neo, S.Y.; Lundquist, J.; Chaabane, W.; Nisancioglu, M.H.; Leiss, L.W.; Östman, A.; Bergh, J.; Sedimbi, S.; Lehti, K.; Lundqvist, A.; Stragliotto, C.L.; Haglund, F.; Ehnman, M. CD11c-CD8 Spatial Cross Presentation: A Novel Approach to Link Immune Surveillance and Patient Survival in Soft Tissue Sarcoma. Cancers 2021, 13, 1175. https://doi.org/10.3390/cancers13051175

AMA Style

Su Y, Tsagkozis P, Papakonstantinou A, Tobin NP, Gultekin O, Malmerfelt A, Ingelshed K, Neo SY, Lundquist J, Chaabane W, Nisancioglu MH, Leiss LW, Östman A, Bergh J, Sedimbi S, Lehti K, Lundqvist A, Stragliotto CL, Haglund F, Ehnman M. CD11c-CD8 Spatial Cross Presentation: A Novel Approach to Link Immune Surveillance and Patient Survival in Soft Tissue Sarcoma. Cancers. 2021; 13(5):1175. https://doi.org/10.3390/cancers13051175

Chicago/Turabian Style

Su, Yanhong, Panagiotis Tsagkozis, Andri Papakonstantinou, Nicholas P. Tobin, Okan Gultekin, Anna Malmerfelt, Katrine Ingelshed, Shi Y. Neo, Johanna Lundquist, Wiem Chaabane, Maya H. Nisancioglu, Lina W. Leiss, Arne Östman, Jonas Bergh, Saikiran Sedimbi, Kaisa Lehti, Andreas Lundqvist, Christina L. Stragliotto, Felix Haglund, and Monika Ehnman. 2021. "CD11c-CD8 Spatial Cross Presentation: A Novel Approach to Link Immune Surveillance and Patient Survival in Soft Tissue Sarcoma" Cancers 13, no. 5: 1175. https://doi.org/10.3390/cancers13051175

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