TY - JOUR
T1 - Recurrent HNSCC harbor an immunosuppressive tumor immune microenvironment suggesting successful tumor immune evasion
AU - Watermann, Christian
AU - Pasternack, Helen
AU - Idel, Christian
AU - Ribbat-Idel, Julika
AU - Bragelmann, Johannes
AU - Kuppler, Patrick
AU - Offermann, Anne
AU - Jonigk, Danny
AU - Kuhnel, Mark Philipp
AU - Schrock, Andreas
AU - Dreyer, Eva
AU - Rosero, Christian
AU - Nathansen, Jacqueline
AU - Dubrovska, Anna
AU - Tharun, Lars
AU - Kirfel, Jutta
AU - Wollenberg, Barbara
AU - Perner, Sven
AU - Krupar, Rosemarie
N1 - Funding Information:
J. Br€agelmann was supported by the Else Kroner-Fresenius Stiftung Memorial Grant (2018_EKMS.35) and the Deutsche Krebshilfe through a Mildred Scheel Nachwuchszentrum Grant (70113307).
Publisher Copyright:
2020 American Association for Cancer Research.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - Purpose: Recurrent tumors (RT) of head and neck squamous cell carcinoma (HNSCC) occur in up to 60%, with poor therapeutic response and detrimental prognosis. We hypothesized that HNSCC RTs successfully evade antitumor immune response and aimed to reveal tumor immune microenvironment (TIME) changes of primary tumors (PT) and corresponding RTs. Experimental Design: Tumor-infiltrating leukocytes (TIL) of 300 PTs and 108 RTs from two large independent and clinically well-characterized HNSCC cohorts [discovery cohort (DC), validation cohort (VD)] were compared by IHC. mRNA expression analysis of 730 immune-related genes was performed for 18 PTs and RTs after adjuvant chemoradiotherapy (CRT). The effect of chemotherapy and radiation resistance was assessed with an in vitro spheroid/immunocyte coculture model. Results: TIME analysis revealed overall decrease of TILs with significant loss of CD8þ T cells (DC P ¼ 0.045/VC P < 0.0001) and B lymphocytes (DC P ¼ 0.036/VC P < 0.0001) in RTs compared with PTs in both cohorts. Decrease predominantly occurred in RTs after CRT. Gene expression analysis confirmed loss of TILs (P ¼ 0.0004) and B lymphocytes (P < 0.0001) and showed relative increase of neutrophils (P ¼ 0.018), macrophages (P < 0.0001), dendritic cells (P ¼ 0.0002), and mast cells (P ¼ 0.0057) as well as lower overall expression of immune-related genes (P ¼ 0.018) in RTs after CRT. Genes involved in B-lymphocyte functions and number of tertiary lymphoid structures showed the strongest decrease. SPP1 and MAPK1 were upregulated in vivo and in vitro, indicating their potential suitability as therapeutic targets in CRT resistance. Conclusions: HNSCC RTs have an immunosuppressive TIME, which is particularly apparent after adjuvant CRT and might substantially contribute to poor therapeutic response and prognosis.
AB - Purpose: Recurrent tumors (RT) of head and neck squamous cell carcinoma (HNSCC) occur in up to 60%, with poor therapeutic response and detrimental prognosis. We hypothesized that HNSCC RTs successfully evade antitumor immune response and aimed to reveal tumor immune microenvironment (TIME) changes of primary tumors (PT) and corresponding RTs. Experimental Design: Tumor-infiltrating leukocytes (TIL) of 300 PTs and 108 RTs from two large independent and clinically well-characterized HNSCC cohorts [discovery cohort (DC), validation cohort (VD)] were compared by IHC. mRNA expression analysis of 730 immune-related genes was performed for 18 PTs and RTs after adjuvant chemoradiotherapy (CRT). The effect of chemotherapy and radiation resistance was assessed with an in vitro spheroid/immunocyte coculture model. Results: TIME analysis revealed overall decrease of TILs with significant loss of CD8þ T cells (DC P ¼ 0.045/VC P < 0.0001) and B lymphocytes (DC P ¼ 0.036/VC P < 0.0001) in RTs compared with PTs in both cohorts. Decrease predominantly occurred in RTs after CRT. Gene expression analysis confirmed loss of TILs (P ¼ 0.0004) and B lymphocytes (P < 0.0001) and showed relative increase of neutrophils (P ¼ 0.018), macrophages (P < 0.0001), dendritic cells (P ¼ 0.0002), and mast cells (P ¼ 0.0057) as well as lower overall expression of immune-related genes (P ¼ 0.018) in RTs after CRT. Genes involved in B-lymphocyte functions and number of tertiary lymphoid structures showed the strongest decrease. SPP1 and MAPK1 were upregulated in vivo and in vitro, indicating their potential suitability as therapeutic targets in CRT resistance. Conclusions: HNSCC RTs have an immunosuppressive TIME, which is particularly apparent after adjuvant CRT and might substantially contribute to poor therapeutic response and prognosis.
UR - http://www.scopus.com/inward/record.url?scp=85100189082&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/311dc8dc-d0c4-3863-9dd0-ddcb3e860aab/
U2 - 10.1158/1078-0432.CCR-20-0197
DO - 10.1158/1078-0432.CCR-20-0197
M3 - Journal articles
AN - SCOPUS:85100189082
SN - 1078-0432
VL - 27
SP - 632
EP - 644
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -