TY - JOUR
T1 - A Systemic Protein Deviation Score Linked to PD-1+ CD8+ T Cell Expansion That Predicts Overall Survival in Diffuse Large B Cell Lymphoma
AU - Ask, Eivind Heggernes
AU - Tschan-Plessl, Astrid
AU - Gjerdingen, Thea Johanne
AU - Sætersmoen, Michelle Lu
AU - Hoel, Hanna Julie
AU - Wiiger, Merete Thune
AU - Olweus, Johanna
AU - Wahlin, Björn E.
AU - Lingjærde, Ole Christian
AU - Horowitz, Amir
AU - Cashen, Amanda
AU - Watkins, Marcus
AU - Fehniger, Todd A.
AU - Holte, Harald
AU - Kolstad, Arne
AU - Malmberg, Karl Johan
N1 - Funding Information:
This work was supported by grants from the Swedish Research Council , the Swedish Children’s Cancer Society , the Swedish Cancer Society , the Tobias Foundation , the Karolinska Institutet , the Wenner-Gren Foundation , the Knut and Alice Wallenberg Foundation (Sweden), the Norwegian Cancer Society , the Research Council of Norway, the South-Eastern Norway Regional Health Authority , and the K.G. Jebsen Center for Cancer Immunotherapy . A.T.P. was supported by a personal grant from the Swiss Cancer League . T.A.F., A.F.C., and the Washington University School of Medicine in St. Louis samples were supported by the Jamie Erin Follicular Lymphoma Fund , the Steinback Fund at the Barnes Jewish Hospital Foundation , and the Siteman Cancer Center Investment Program ( P30CA091842 ).
Funding Information:
This work was supported by grants from the Swedish Research Council, the Swedish Children's Cancer Society, the Swedish Cancer Society, the Tobias Foundation, the Karolinska Institutet, the Wenner-Gren Foundation, the Knut and Alice Wallenberg Foundation (Sweden), the Norwegian Cancer Society, the Research Council of Norway, the South-Eastern Norway Regional Health Authority, and the K.G. Jebsen Center for Cancer Immunotherapy. A.T.P. was supported by a personal grant from the Swiss Cancer League. T.A.F. A.F.C. and the Washington University School of Medicine in St. Louis samples were supported by the Jamie Erin Follicular Lymphoma Fund, the Steinback Fund at the Barnes Jewish Hospital Foundation, and the Siteman Cancer Center Investment Program (P30CA091842). A.T.-P. and E.H.A. conducted the experiments and analyzed the data. E.H.A. and O.C.L. performed and reviewed the statistical analyses, respectively. M.L.S. and A.H. contributed to the experimental design. J.O. A.F.C. T.J.G. M.T.W. and H.J.H. contributed by organizing the biobanks. A.K. H.H. B.E.W. T.A.F. and M.W. provided clinical data and input on the study design. A.T.-P. E.H.A. and K.-J.M. designed the research and wrote the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/2/12
Y1 - 2021/2/12
N2 - Background: Current prognostic variables can only partly explain the large outcome heterogeneity in diffuse large B cell lymphoma (DLBCL). We aimed to investigate the utility of systems-level protein and immune repertoire profiling for outcome prognostication in DLBCL. Methods: In this retrospective study, we used proximity extension assay technology to quantify 81 immune-related proteins in serum or plasma in 2 independent cohorts in a total 111 DLBCL patients. Protein levels were assessed before and after treatment with rituximab and chemotherapy, and the patients were compared with 19 age- and sex-matched healthy blood donors. In a subset of the patients, we performed a broad mass cytometric characterization of immune cell repertoires in peripheral blood. Findings: Patients displayed large deviations in protein profiles compared with healthy controls. Development of a systemic protein deviation (SPD) score provided a 4-protein-based metric that reflected the overall degree of protein deviations compared with age- and sex-matched healthy blood donors. The SPD score identified patients with very poor overall survival in both cohorts and correlated with increased frequencies of peripheral blood PD-1+ CD8+ T cells, and expansion of myeloid-derived suppressor cells. Conclusions: Our results show that a simple metric based on measurement of a small set of serum or plasma proteins can be used to probe systemic immune changes associated with poor survival in DLBCL. This finding warrants further investigation in larger, prospective studies to establish a clinical prognostic biomarker.
AB - Background: Current prognostic variables can only partly explain the large outcome heterogeneity in diffuse large B cell lymphoma (DLBCL). We aimed to investigate the utility of systems-level protein and immune repertoire profiling for outcome prognostication in DLBCL. Methods: In this retrospective study, we used proximity extension assay technology to quantify 81 immune-related proteins in serum or plasma in 2 independent cohorts in a total 111 DLBCL patients. Protein levels were assessed before and after treatment with rituximab and chemotherapy, and the patients were compared with 19 age- and sex-matched healthy blood donors. In a subset of the patients, we performed a broad mass cytometric characterization of immune cell repertoires in peripheral blood. Findings: Patients displayed large deviations in protein profiles compared with healthy controls. Development of a systemic protein deviation (SPD) score provided a 4-protein-based metric that reflected the overall degree of protein deviations compared with age- and sex-matched healthy blood donors. The SPD score identified patients with very poor overall survival in both cohorts and correlated with increased frequencies of peripheral blood PD-1+ CD8+ T cells, and expansion of myeloid-derived suppressor cells. Conclusions: Our results show that a simple metric based on measurement of a small set of serum or plasma proteins can be used to probe systemic immune changes associated with poor survival in DLBCL. This finding warrants further investigation in larger, prospective studies to establish a clinical prognostic biomarker.
KW - CD8 T cells
KW - CyTOF
KW - DLBCL
KW - PD-1
KW - Translation to Patients
KW - biomarker
KW - myeloid derived suppressor cells
KW - proteomics
KW - systems immunology
UR - http://www.scopus.com/inward/record.url?scp=85108552580&partnerID=8YFLogxK
U2 - 10.1016/j.medj.2020.10.006
DO - 10.1016/j.medj.2020.10.006
M3 - Article
C2 - 35590201
AN - SCOPUS:85108552580
SN - 2666-6359
VL - 2
SP - 180-195.e5
JO - Med
JF - Med
IS - 2
ER -