Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy

Rajasekharan Somasundaram; Thomas Connelly; Robin Choi; Hyeree Choi; Anastasia Samarkina; Ling Li; Elizabeth Gregorio; Yeqing Chen; Rohit Thakur; Mohamed Abdel-Mohsen; Marilda Beqiri; Meaghan Kiernan; Michela Perego; Fang Wang; Min Xiao; Patricia Brafford; Xue Yang; Xiaowei Xu; Anthony Secreto; Gwenn Danet-Desnoyers; Daniel Traum; Klaus H. Kaestner; Alexander C. Huang; Denitsa Hristova; Joshua Wang; Mizuho Fukunaga-Kalabis; Clemens Krepler; Fang Ping-Chen; Xiangyang Zhou; Alexis Gutierrez; Vito W. Rebecca; Prashanthi Vonteddu; Farokh Dotiwala; Shashi Bala; Sonali Majumdar; Harsh Dweep; Jayamanna Wickramasinghe; Andrew V. Kossenkov; Jorge Reyes-Arbujas; Kenisha Santiago; Tran Nguyen; Johannes Griss; Frederick Keeney; James Hayden; Brian J. Gavin; David Weiner; Luis J. Montaner; Qin Liu; Lukas Peiffer; Jürgen Becker; Elizabeth M. Burton; Michael A. Davies; Michael T. Tetzlaff; Kar Muthumani; Jennifer A. Wargo; Dmitry Gabrilovich; Meenhard Herlyn

doi:10.1038/s41467-020-20600-7

Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy

Rajasekharan Somasundaram, Thomas Connelly, Robin Choi, Hyeree Choi, Anastasia Samarkina, Ling Li, Elizabeth Gregorio, Yeqing Chen, Rohit Thakur, Mohamed Abdel-Mohsen, Marilda Beqiri, Meaghan Kiernan, Michela Perego, Fang Wang, Min Xiao, Patricia Brafford, Xue Yang, Xiaowei Xu, Anthony Secreto, Gwenn Danet-DesnoyersDaniel Traum, Klaus H. Kaestner, Alexander C. Huang, Denitsa Hristova, Joshua Wang, Mizuho Fukunaga-Kalabis, Clemens Krepler, Fang Ping-Chen, Xiangyang Zhou, Alexis Gutierrez, Vito W. Rebecca, Prashanthi Vonteddu, Farokh Dotiwala, Shashi Bala, Sonali Majumdar, Harsh Dweep, Jayamanna Wickramasinghe, Andrew V. Kossenkov, Jorge Reyes-Arbujas, Kenisha Santiago, Tran Nguyen, Johannes Griss, Frederick Keeney, James Hayden, Brian J. Gavin, David Weiner, Luis J. Montaner, Qin Liu, Lukas Peiffer, Jürgen Becker, Elizabeth M. Burton, Michael A. Davies, Michael T. Tetzlaff, Kar Muthumani, Jennifer A. Wargo, Dmitry Gabrilovich, Meenhard Herlyn

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

4 Scopus citations

Abstract

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34⁺ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγ^null (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3⁺ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8⁺/Granz B⁺ T cells homeostasis are observed in tumor regions where FOXP3⁺ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

Original language	English (US)
Article number	346
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20600-7
State	Published - Dec 1 2021
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-020-20600-7

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Somasundaram, R., Connelly, T., Choi, R., Choi, H., Samarkina, A., Li, L., Gregorio, E., Chen, Y., Thakur, R., Abdel-Mohsen, M., Beqiri, M., Kiernan, M., Perego, M., Wang, F., Xiao, M., Brafford, P., Yang, X., Xu, X., Secreto, A., ... Herlyn, M. (2021). Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. Nature communications, 12(1), Article 346. https://doi.org/10.1038/s41467-020-20600-7

Somasundaram, R, Connelly, T, Choi, R, Choi, H, Samarkina, A, Li, L, Gregorio, E, Chen, Y, Thakur, R, Abdel-Mohsen, M, Beqiri, M, Kiernan, M, Perego, M, Wang, F, Xiao, M, Brafford, P, Yang, X, Xu, X, Secreto, A, Danet-Desnoyers, G, Traum, D, Kaestner, KH, Huang, AC, Hristova, D, Wang, J, Fukunaga-Kalabis, M, Krepler, C, Ping-Chen, F, Zhou, X, Gutierrez, A, Rebecca, VW, Vonteddu, P, Dotiwala, F, Bala, S, Majumdar, S, Dweep, H, Wickramasinghe, J, Kossenkov, AV, Reyes-Arbujas, J, Santiago, K, Nguyen, T, Griss, J, Keeney, F, Hayden, J, Gavin, BJ, Weiner, D, Montaner, LJ, Liu, Q, Peiffer, L, Becker, J, Burton, EM, Davies, MA, Tetzlaff, MT, Muthumani, K, Wargo, JA, Gabrilovich, D & Herlyn, M 2021, 'Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy', Nature communications, vol. 12, no. 1, 346. https://doi.org/10.1038/s41467-020-20600-7

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title = "Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy",

abstract = "Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.",

author = "Rajasekharan Somasundaram and Thomas Connelly and Robin Choi and Hyeree Choi and Anastasia Samarkina and Ling Li and Elizabeth Gregorio and Yeqing Chen and Rohit Thakur and Mohamed Abdel-Mohsen and Marilda Beqiri and Meaghan Kiernan and Michela Perego and Fang Wang and Min Xiao and Patricia Brafford and Xue Yang and Xiaowei Xu and Anthony Secreto and Gwenn Danet-Desnoyers and Daniel Traum and Kaestner, {Klaus H.} and Huang, {Alexander C.} and Denitsa Hristova and Joshua Wang and Mizuho Fukunaga-Kalabis and Clemens Krepler and Fang Ping-Chen and Xiangyang Zhou and Alexis Gutierrez and Rebecca, {Vito W.} and Prashanthi Vonteddu and Farokh Dotiwala and Shashi Bala and Sonali Majumdar and Harsh Dweep and Jayamanna Wickramasinghe and Kossenkov, {Andrew V.} and Jorge Reyes-Arbujas and Kenisha Santiago and Tran Nguyen and Johannes Griss and Frederick Keeney and James Hayden and Gavin, {Brian J.} and David Weiner and Montaner, {Luis J.} and Qin Liu and Lukas Peiffer and J{\"u}rgen Becker and Burton, {Elizabeth M.} and Davies, {Michael A.} and Tetzlaff, {Michael T.} and Kar Muthumani and Wargo, {Jennifer A.} and Dmitry Gabrilovich and Meenhard Herlyn",

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doi = "10.1038/s41467-020-20600-7",

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AU - Somasundaram, Rajasekharan

AU - Connelly, Thomas

AU - Choi, Robin

AU - Choi, Hyeree

AU - Samarkina, Anastasia

AU - Li, Ling

AU - Gregorio, Elizabeth

AU - Chen, Yeqing

AU - Thakur, Rohit

AU - Abdel-Mohsen, Mohamed

AU - Beqiri, Marilda

AU - Kiernan, Meaghan

AU - Perego, Michela

AU - Wang, Fang

AU - Xiao, Min

AU - Brafford, Patricia

AU - Yang, Xue

AU - Xu, Xiaowei

AU - Secreto, Anthony

AU - Danet-Desnoyers, Gwenn

AU - Traum, Daniel

AU - Kaestner, Klaus H.

AU - Huang, Alexander C.

AU - Hristova, Denitsa

AU - Wang, Joshua

AU - Fukunaga-Kalabis, Mizuho

AU - Krepler, Clemens

AU - Ping-Chen, Fang

AU - Zhou, Xiangyang

AU - Gutierrez, Alexis

AU - Rebecca, Vito W.

AU - Vonteddu, Prashanthi

AU - Dotiwala, Farokh

AU - Bala, Shashi

AU - Majumdar, Sonali

AU - Dweep, Harsh

AU - Wickramasinghe, Jayamanna

AU - Kossenkov, Andrew V.

AU - Reyes-Arbujas, Jorge

AU - Santiago, Kenisha

AU - Nguyen, Tran

AU - Griss, Johannes

AU - Keeney, Frederick

AU - Hayden, James

AU - Gavin, Brian J.

AU - Weiner, David

AU - Montaner, Luis J.

AU - Liu, Qin

AU - Peiffer, Lukas

AU - Becker, Jürgen

AU - Burton, Elizabeth M.

AU - Davies, Michael A.

AU - Tetzlaff, Michael T.

AU - Muthumani, Kar

AU - Wargo, Jennifer A.

AU - Gabrilovich, Dmitry

AU - Herlyn, Meenhard

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

AB - Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy

Abstract

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