1. Blocking IL1 Beta Promotes Tumor Regression and Remodeling of the Myeloid Compartment in a Renal Cell Carcinoma Model: Multidimensional Analyses
- Author
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David H. Aggen, Casey Ager, Hu Li, Matthew G. Chaimowitz, Zoila A. Lopez-Bujanda, Xinzheng V. Guo, Catherine S. Spina, Cheng Zhang, Nivedita Chowdhury, Aleksandar Obradovic, Matthew Dallos, Vinson Wang, Wendy Mao, Ali Ghasemzadeh, Charles G. Drake, and Jessica Hawley
- Subjects
0301 basic medicine ,Cancer Research ,Myeloid ,Cabozantinib ,medicine.drug_class ,Pyridines ,medicine.medical_treatment ,T cell ,Interleukin-1beta ,Tyrosine-kinase inhibitor ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Tumor-Associated Macrophages ,medicine ,Animals ,Humans ,Anilides ,RNA-Seq ,Carcinoma, Renal Cell ,Immune Checkpoint Inhibitors ,Mice, Inbred BALB C ,Innate immune system ,Chemistry ,Myeloid-Derived Suppressor Cells ,Immunosuppression ,Immunotherapy ,medicine.disease ,Kidney Neoplasms ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Cytokines ,Female ,Single-Cell Analysis ,Kidney cancer - Abstract
Purpose: Intratumoral immunosuppression mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) represents a potential mechanism of immune checkpoint inhibitor (ICI) resistance in solid tumors. By promoting TAM and MDSC infiltration, IL1β may drive adaptive and innate immune resistance in renal cell carcinoma (RCC) and in other tumor types. Experimental Design: Using the RENCA model of RCC, we evaluated clinically relevant combinations of anti-IL1β plus either anti-PD-1 or the multitargeted tyrosine kinase inhibitor (TKI), cabozantinib. We performed comprehensive immune profiling of established RENCA tumors via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing (RNA-seq). Similar analyses were extended to the MC38 tumor model. Results: Analyses via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA-seq showed that anti-IL1β reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1β plus anti-PD-1 or cabozantinib showed increased antitumor activity that was associated with decreases in immunosuppressive MDSCs and increases in M1-like TAMs. Conclusions: Single-cell RNA-seq analyses show that IL1β blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell–independent mechanisms. IL1β is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
- Published
- 2020