TY - JOUR
T1 - Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
AU - Gutwillig, Amit
AU - Santana-Magal, Nadine
AU - Farhat-Younis, Leen
AU - Rasoulouniriana, Diana
AU - Madi, Asaf
AU - Luxenburg, Chen
AU - Cohen, Jonathan
AU - Padmanabhan, Krishnanand
AU - Shomron, Noam
AU - Shapira, Guy
AU - Gleiberman, Annette
AU - Parikh, Roma
AU - Levy, Carmit
AU - Feinmesser, Meora
AU - Hershkovitz, Dov
AU - Zemser-Werner, Valentina
AU - Zlotnik, Oran
AU - Kroon, Sanne
AU - Hardt, Wolf Dietrich
AU - Debets, Reno
AU - Reticker-Flynn, Nathan Edward
AU - Rider, Peleg
AU - Carmi, Yaron
N1 - Publisher Copyright:
© Gutwillig et al.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and acti-vator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhib-iting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity.
AB - Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and acti-vator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhib-iting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity.
UR - http://www.scopus.com/inward/record.url?scp=85138210644&partnerID=8YFLogxK
U2 - 10.7554/ELIFE.80315
DO - 10.7554/ELIFE.80315
M3 - Article
C2 - 36124553
AN - SCOPUS:85138210644
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e80315
ER -