Journal Article
. 2021 Mar; 206(8):1966-1975.
doi: 10.4049/jimmunol.2000523.

IL-1α Mediates Innate and Acquired Resistance to Immunotherapy in Melanoma

Shubhra Singh 1 Zhilan Xiao 2 Karishma Bavisi 1 Jason Roszik 2 Brenda D Melendez 3 Zhiqiang Wang 4 Mark J Cantwell 5 Richard E Davis 1 Greg Lizee 2 Patrick Hwu 2 Sattva S Neelapu 1 Willem W Overwijk 6 Manisha Singh 7 
  • PMID: 33722878
  •     36 References
  •     3 citations


Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.

Proinflammatory cytokines.
C A Dinarello.
Chest, 2000 Aug 11; 118(2). PMID: 10936147
Highly Cited. Review.
Cutaneous melanoma.
Vincenzo de Giorgi, Emanuele Crocetti, Paolo Carli.
Lancet, 2005 Jun 14; 365(9476). PMID: 15950709
Myeloid-derived suppressor cells in malignant melanoma.
Viktor Umansky, Alexandra Sevko, Christoffer Gebhardt, Jochen Utikal.
J Dtsch Dermatol Ges, 2014 Sep 30; 12(11). PMID: 25263083
IL-1α modulates neutrophil recruitment in chronic inflammation induced by hydrocarbon oil.
Pui Y Lee, Yutaro Kumagai, +8 authors, Westley H Reeves.
J Immunol, 2010 Dec 31; 186(3). PMID: 21191074    Free PMC article.
Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity.
Masashi Ikutani, Tsutomu Yanagibashi, +8 authors, Kiyoshi Takatsu.
J Immunol, 2011 Dec 17; 188(2). PMID: 22174445
Highly Cited.
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.
Willy Hugo, Jesse M Zaretsky, +15 authors, Roger S Lo.
Cell, 2017 Jan 28; 168(3). PMID: 28129544
Highly Cited.
Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain.
Manisha Singh, Christina Vianden, +15 authors, Willem W Overwijk.
Nat Commun, 2017 Nov 14; 8(1). PMID: 29129918    Free PMC article.
CD40 Agonist Antibodies in Cancer Immunotherapy.
Robert H Vonderheide.
Annu Rev Med, 2019 Aug 15; 71. PMID: 31412220
Highly Cited. Review.
Blocking IL1 Beta Promotes Tumor Regression and Remodeling of the Myeloid Compartment in a Renal Cell Carcinoma Model: Multidimensional Analyses.
David H Aggen, Casey R Ager, +13 authors, Charles G Drake.
Clin Cancer Res, 2020 Nov 06; 27(2). PMID: 33148676    Free PMC article.
IL-1 is required for tumor invasiveness and angiogenesis.
Elena Voronov, Dror S Shouval, +5 authors, Ron N Apte.
Proc Natl Acad Sci U S A, 2003 Feb 25; 100(5). PMID: 12598651    Free PMC article.
Highly Cited.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
Freddie Bray, Jacques Ferlay, +3 authors, Ahmedin Jemal.
CA Cancer J Clin, 2018 Sep 13; 68(6). PMID: 30207593
Highly Cited.
Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.
David Dankort, David P Curley, +7 authors, Marcus Bosenberg.
Nat Genet, 2009 Mar 14; 41(5). PMID: 19282848    Free PMC article.
Highly Cited.
Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients.
Priyanka B Subrahmanyam, Zhiwan Dong, +7 authors, F Stephen Hodi.
J Immunother Cancer, 2018 Mar 08; 6(1). PMID: 29510697    Free PMC article.
Highly Cited.
The New Era of Cancer Immunotherapy: Targeting Myeloid-Derived Suppressor Cells to Overcome Immune Evasion.
Paola De Cicco, Giuseppe Ercolano, Angela Ianaro.
Front Immunol, 2020 Aug 28; 11. PMID: 32849585    Free PMC article.
Constitutive aberrant endogenous interleukin-1 facilitates inflammation and growth in human melanoma.
Yong Qin, Suhendan Ekmekcioglu, +4 authors, Elizabeth A Grimm.
Mol Cancer Res, 2011 Sep 29; 9(11). PMID: 21954434    Free PMC article.
Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy.
Yared Hailemichael, Amber Woods, +17 authors, Willem W Overwijk.
J Clin Invest, 2018 Feb 27; 128(4). PMID: 29480817    Free PMC article.
Highly Cited.
Melanoma-derived IL-1 converts vascular endothelium to a proinflammatory and procoagulatory phenotype via NFκB activation.
Elwira A Strozyk, Anna Desch, +4 authors, Stefan W Schneider.
Exp Dermatol, 2014 Jul 22; 23(9). PMID: 25041487
Response assessment in metastatic melanoma treated with ipilimumab and bevacizumab: CT tumor size and density as markers for response and outcome.
Mizuki Nishino, Anita Giobbie-Hurder, Nikhil H Ramaiya, F Stephen Hodi.
J Immunother Cancer, 2014 Nov 21; 2(1). PMID: 25411640    Free PMC article.
Next generation of immune checkpoint therapy in cancer: new developments and challenges.
Julian A Marin-Acevedo, Bhagirathbhai Dholaria, +3 authors, Yanyan Lou.
J Hematol Oncol, 2018 Mar 17; 11(1). PMID: 29544515    Free PMC article.
Highly Cited. Review.
Costimulatory effects of IL-1 on the expansion/differentiation of CD4+CD25+Foxp3+ and CD4+CD25+Foxp3- T cells.
Carine Brinster, Ethan M Shevach.
J Leukoc Biol, 2008 May 15; 84(2). PMID: 18477692    Free PMC article.
Agonistic CD40 antibodies and cancer therapy.
Robert H Vonderheide, Martin J Glennie.
Clin Cancer Res, 2013 Mar 06; 19(5). PMID: 23460534    Free PMC article.
Highly Cited.
Elevated chronic inflammatory factors and myeloid-derived suppressor cells indicate poor prognosis in advanced melanoma patients.
Huanhuan Jiang, Christoffer Gebhardt, +4 authors, Viktor Umansky.
Int J Cancer, 2014 Oct 30; 136(10). PMID: 25353097
The in vivo expansion rate of properly stimulated transferred CD8+ T cells exceeds that of an aggressively growing mouse tumor.
Leroy N Hwang, Zhiya Yu, Douglas C Palmer, Nicholas P Restifo.
Cancer Res, 2006 Jan 21; 66(2). PMID: 16424050    Free PMC article.
Cluster analysis and display of genome-wide expression patterns.
M B Eisen, P T Spellman, P O Brown, D Botstein.
Proc Natl Acad Sci U S A, 1998 Dec 09; 95(25). PMID: 9843981    Free PMC article.
Highly Cited.
The Emerging Therapeutic Landscape of Advanced Melanoma.
Vanessa Henriques, Teresa Martins, Wolfgang Link, Bibiana I Ferreira.
Curr Pharm Des, 2018 Jan 26; 24(5). PMID: 29366407
Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors.
Rebekka Weber, Viktor Fleming, +5 authors, Viktor Umansky.
Front Immunol, 2018 Jun 27; 9. PMID: 29942309    Free PMC article.
Highly Cited. Review.
Inflammation and cancer: an ancient link with novel potentials.
S Perwez Hussain, Curtis C Harris.
Int J Cancer, 2007 Sep 26; 121(11). PMID: 17893866
Highly Cited. Review.
Anakinra Therapy for Non-cancer Inflammatory Diseases.
Giulio Cavalli, Charles A Dinarello.
Front Pharmacol, 2018 Nov 22; 9. PMID: 30459597    Free PMC article.
Highly Cited. Review.
β-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas.
William E Damsky, David P Curley, +8 authors, Marcus Bosenberg.
Cancer Cell, 2011 Dec 17; 20(6). PMID: 22172720    Free PMC article.
Highly Cited.
Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.
Willem W Overwijk, Marc R Theoret, +15 authors, Nicholas P Restifo.
J Exp Med, 2003 Aug 20; 198(4). PMID: 12925674    Free PMC article.
Highly Cited.
Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards.
Vincenzo Bronte, Sven Brandau, +12 authors, Dmitry I Gabrilovich.
Nat Commun, 2016 Jul 07; 7. PMID: 27381735    Free PMC article.
Highly Cited. Review.
Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
Weiyi Peng, Jie Qing Chen, +41 authors, Patrick Hwu.
Cancer Discov, 2015 Dec 10; 6(2). PMID: 26645196    Free PMC article.
Highly Cited.
Immunotherapy in melanoma: Recent advances and future directions.
C Franklin, E Livingstone, +2 authors, D Schadendorf.
Eur J Surg Oncol, 2016 Oct 23; 43(3). PMID: 27769635
Highly Cited. Review.
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.
Itay Tirosh, Benjamin Izar, +34 authors, Levi A Garraway.
Science, 2016 Apr 29; 352(6282). PMID: 27124452    Free PMC article.
Highly Cited.
Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells.
Arnaud Pommier, Alexandra Audemard, +10 authors, Armelle Prévost-Blondel.
Proc Natl Acad Sci U S A, 2013 Jul 24; 110(32). PMID: 23878221    Free PMC article.
The Immune Function of Ly6Chi Inflammatory Monocytes During Infection and Inflammation.
L Liu, Y Wei, X Wei.
Curr Mol Med, 2017 Feb 25; 17(1). PMID: 28231755
miRNA as a Modulator of Immunotherapy and Immune Response in Melanoma.
Mai-Huong Thi Nguyen, Yueh-Hsia Luo, +4 authors, Nianhan Ma.
Biomolecules, 2021 Nov 28; 11(11). PMID: 34827646    Free PMC article.
Improving cancer immunotherapy by targeting IL-1.
Zhilan Xiao, Shubhra Singh, Manisha Singh.
Oncoimmunology, 2021 Dec 04; 10(1). PMID: 34858734    Free PMC article.
Potential therapies for immune-related adverse events associated with immune checkpoint inhibition: from monoclonal antibodies to kinase inhibition.
Meagan-Helen Henderson Berg, Sonia Victoria Del Rincón, Wilson H Miller.
J Immunother Cancer, 2022 Jan 29; 10(1). PMID: 35086945    Free PMC article.