TY - JOUR
T1 - Blocking IL1 beta promotes tumor regression and remodeling of the myeloid compartment in a renal cell carcinoma model
T2 - multidimensional analyses
AU - Aggen, David H.
AU - Ager, Casey R.
AU - Obradovic, Aleksandar Z.
AU - Chowdhury, Nivedita
AU - Ghasemzadeh, Ali
AU - Mao, Wendy
AU - Chaimowitz, Matthew G.
AU - Lopez-Bujanda, Zoila A.
AU - Spina, Catherine S.
AU - Hawley, Jessica E.
AU - Dallos, Matthew C.
AU - Zhang, Cheng
AU - Wang, Vinson
AU - Li, Hu
AU - Guo, Xinzheng V.
AU - Drake, Charles G.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - 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, IL1b 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-IL1b 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-IL1b reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1b 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 IL1b blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell–independent mechanisms. IL1b is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
AB - 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, IL1b 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-IL1b 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-IL1b reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1b 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 IL1b blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell–independent mechanisms. IL1b is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
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U2 - 10.1158/1078-0432.CCR-20-1610
DO - 10.1158/1078-0432.CCR-20-1610
M3 - Article
C2 - 33148676
AN - SCOPUS:85100351465
SN - 1078-0432
VL - 27
SP - 608
EP - 621
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -