Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors

Xianda Zhao; Beminet Kassaye; Dechen Wangmo; Emil Lou; Subbaya Subramanian

doi:10.1016/j.isci.2020.101056

Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors

Xianda Zhao, Beminet Kassaye, Dechen Wangmo, Emil Lou, Subbaya Subramanian

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Immunotherapies are used as adjuvant therapies for cancers. However, knowledge of how traditional cancer treatments affect immunotherapies is limited. Using mouse models, we demonstrate that tumor-draining lymph nodes (TdLNs) are critical for tumor antigen-specific T cell response. However, removing TdLNs concurrently with established primary tumors did not affect the immune checkpoint blockade (ICB) response on localized secondary tumor due to immunotolerance in TdLNs and distribution of antigen-specific T cells in peripheral lymphatic organs. Notably, treatment response improved with sequential administration of 5-fluorouracil (5-FU) and ICB compared with concurrent administration of ICB with 5-FU. Immune profiling revealed that using 5-FU as induction treatment increased tumor visibility to immune cells, decreased immunosuppressive cells in the tumor microenvironment, and limited chemotherapy-induced T cell depletion. We show that the effect of traditional cytotoxic treatment, not TdLNs, influences immunotherapy response in localized secondary tumors. We postulate essential considerations for successful immunotherapy strategies in clinical conditions.

Original language	English (US)
Article number	101056
Journal	iScience
Volume	23
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2020.101056
State	Published - May 22 2020

Bibliographical note

Funding Information:
This work is supported by the Minnesota Colorectal Cancer Research Funds, Mezin-Koats Colon Cancer Research Award and the ChainBreaker funds from Masonic Cancer Center, University of Minnesota, and University of Minnesota, Medical School Innovation award and the Department of Surgery, Research funds. We thank the Mass Cytometry core facility at University of Minnesota for helpful assistance. We thank Dr. Matthew Robertson and Ms. Isabella Ramirez for assisting with manuscript editing. X.Z. and S.S. conceived and designed the experiments. X.Z. B.K. and D.W. performed all experiments and data analyses. X.Z. B.K. D.W. E.L. and S.S. commented on the data and co-wrote the paper. S.S. supervised this project. The authors declare no competing interests.

Funding Information:
This work is supported by the Minnesota Colorectal Cancer Research Funds , Mezin-Koats Colon Cancer Research Award and the ChainBreaker funds from Masonic Cancer Center, University of Minnesota , and University of Minnesota , Medical School Innovation award and the Department of Surgery , Research funds. We thank the Mass Cytometry core facility at University of Minnesota for helpful assistance. We thank Dr. Matthew Robertson and Ms. Isabella Ramirez for assisting with manuscript editing.

Publisher Copyright:
© 2020 The Authors

Keywords

Biological Sciences
Cancer
Immune Response
Therapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors",

abstract = "Immunotherapies are used as adjuvant therapies for cancers. However, knowledge of how traditional cancer treatments affect immunotherapies is limited. Using mouse models, we demonstrate that tumor-draining lymph nodes (TdLNs) are critical for tumor antigen-specific T cell response. However, removing TdLNs concurrently with established primary tumors did not affect the immune checkpoint blockade (ICB) response on localized secondary tumor due to immunotolerance in TdLNs and distribution of antigen-specific T cells in peripheral lymphatic organs. Notably, treatment response improved with sequential administration of 5-fluorouracil (5-FU) and ICB compared with concurrent administration of ICB with 5-FU. Immune profiling revealed that using 5-FU as induction treatment increased tumor visibility to immune cells, decreased immunosuppressive cells in the tumor microenvironment, and limited chemotherapy-induced T cell depletion. We show that the effect of traditional cytotoxic treatment, not TdLNs, influences immunotherapy response in localized secondary tumors. We postulate essential considerations for successful immunotherapy strategies in clinical conditions.",

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author = "Xianda Zhao and Beminet Kassaye and Dechen Wangmo and Emil Lou and Subbaya Subramanian",

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AU - Lou, Emil

AU - Subramanian, Subbaya

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N2 - Immunotherapies are used as adjuvant therapies for cancers. However, knowledge of how traditional cancer treatments affect immunotherapies is limited. Using mouse models, we demonstrate that tumor-draining lymph nodes (TdLNs) are critical for tumor antigen-specific T cell response. However, removing TdLNs concurrently with established primary tumors did not affect the immune checkpoint blockade (ICB) response on localized secondary tumor due to immunotolerance in TdLNs and distribution of antigen-specific T cells in peripheral lymphatic organs. Notably, treatment response improved with sequential administration of 5-fluorouracil (5-FU) and ICB compared with concurrent administration of ICB with 5-FU. Immune profiling revealed that using 5-FU as induction treatment increased tumor visibility to immune cells, decreased immunosuppressive cells in the tumor microenvironment, and limited chemotherapy-induced T cell depletion. We show that the effect of traditional cytotoxic treatment, not TdLNs, influences immunotherapy response in localized secondary tumors. We postulate essential considerations for successful immunotherapy strategies in clinical conditions.

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Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors

Abstract

Bibliographical note

Keywords

UN SDGs

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