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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:BackgroundModulation 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.MethodsWe 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.ResultsWe 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-?B-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.ConclusionsCollectively, 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.

Project description:Background:Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). Methods:To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti-PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro. Results:Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation. Conclusion:Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.

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

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

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