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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 IL2R?^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.

SUBMITTER: Somasundaram R

PROVIDER: S-EPMC7804257 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

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

Nature communications 20210112 1

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<sup>+</sup> cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγ<sup>null</sup> (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 reg ...[more]

PMID: 33436641

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Project description:Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs. Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.

Dataset Information

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

Publications

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

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