Abstract
Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.
Key points
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In any particular cell, the expression of a given protein fluctuates dynamically around a pre-set homeostatic level, contributing to temporal heterogeneity. At the cell-population level, the expression of a given protein fits a log-normal distribution, contributing to spatial heterogeneity.
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Cell state is mostly determined by the expression levels of different proteins, which is a continuous quantitative variable and can be perturbed by extrinsic stress, such as drug exposure.
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The development of resistance to targeted therapy and immunotherapy can be divided into three phases, namely, early survival (including persister cells and innate resistant cells), reversal of senescence and new homeostasis; along these phases, resistance gradually changes from reversible to irreversible.
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The persister cell subpopulation is programmed to tolerate cell death and capable of surviving harsh environmental conditions, such as hypoxia, lack of nutrients and exposure to targeted therapy and/or immunotherapy.
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Future therapeutic developments should take into account the highly dynamic heterogeneity and the existence of distinct homeostatic states of tumour cells.
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References
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29 (2015).
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 66, 7–30 (2016).
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 67, 7–30 (2017).
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).
Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).
Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012).
Larkin, J. et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 371, 1867–1876 (2014).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
Sullivan, R. J. & Flaherty, K. T. Resistance to BRAF-targeted therapy in melanoma. Eur. J. Cancer 49, 1297–1304 (2013).
Ribas, A. et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 315, 1600–1609 (2016).
Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).
Hugo, W. et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162, 1271–1285 (2015).
Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).
Fallahi-Sichani, M. et al. Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol. Syst. Biol. 13, 905 (2017).
Ravindran Menon, D. et al. A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 34, 4448–4459 (2015).
Chen, L., Heymach, J. V., Qin, F. X. & Gibbons, D. L. The mutually regulatory loop of epithelial-mesenchymal transition and immunosuppression in cancer progression. Oncoimmunology 4, e1002731 (2015).
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).
Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
Gupta, P. B., Chaffer, C. L. & Weinberg, R. A. Cancer stem cells: mirage or reality? Nat. Med. 15, 1010–1012 (2009).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Zabierowski, S. E. & Herlyn, M. Melanoma stem cells: the dark seed of melanoma. J. Clin. Oncol. 26, 2890–2894 (2008).
Schatton, T. et al. Identification of cells initiating human melanomas. Nature 451, 345–349 (2008).
Schatton, T., Frank, N. Y. & Frank, M. H. Identification and targeting of cancer stem cells. Bioessays 31, 1038–1049 (2009).
Kemper, K., de Goeje, P. L., Peeper, D. S. & van Amerongen, R. Phenotype switching: tumor cell plasticity as a resistance mechanism and target for therapy. Cancer Res. 74, 5937–5941 (2014).
Hoek, K. S. et al. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment Cell Res. 19, 290–302 (2006).
Zipser, M. C. et al. A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status. Pigment Cell Melanoma Res. 24, 326–333 (2011).
Wellbrock, C. & Arozarena, I. Microphthalmia-associated transcription factor in melanoma development and MAP-kinase pathway targeted therapy. Pigment Cell Melanoma Res. 28, 390–406 (2015).
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
Cho, H. I., Lee, Y. R. & Celis, E. Interferon gamma limits the effectiveness of melanoma peptide vaccines. Blood 117, 135–144 (2011).
Nowicki, T. S., Hu-Lieskovan, S. & Ribas, A. Mechanisms of resistance to PD-1 and PD-L1 Blockade. Cancer J. 24, 47–53 (2018).
Sucker, A. et al. Acquired IFNgamma resistance impairs anti-tumor immunity and gives rise to T cell-resistant melanoma lesions. Nat. Commun. 8, 15440 (2017).
Tsoi, J. et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell 33, 890–904 (2018).
Mehta, A. et al. Immunotherapy resistance by inflammation-induced dedifferentiation. Cancer Discov. 8, 935–943 (2018).
Zha, Z. et al. Interferon-gamma is a master checkpoint regulator of cytokine-induced differentiation. Proc. Natl Acad. Sci. USA 114, E6867–E6874 (2017).
Buszczak, M., Signer, R. A. & Morrison, S. J. Cellular differences in protein synthesis regulate tissue homeostasis. Cell 159, 242–251 (2014).
Huang, S. Genetic and non-genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells. Cancer Metastasis Rev. 32, 423–448 (2013).
Brock, A. & Huang, S. Precision oncology: between vaguely right and precisely wrong. Cancer Res. 77, 6473–6479 (2017).
Zhou, H., Neelakantan, D. & Ford, H. L. Clonal cooperativity in heterogenous cancers. Semin. Cell Dev. Biol. 64, 79–89 (2017).
Raj, A. & van Oudenaarden, A. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216–226 (2008).
Frank, S. A. & Rosner, M. R. Nonheritable cellular variability accelerates the evolutionary processes of cancer. PLOS Biol. 10, e1001296 (2012).
Niepel, M., Spencer, S. L. & Sorger, P. K. Non-genetic cell-to-cell variability and the consequences for pharmacology. Curr. Opin. Chem. Biol. 13, 556–561 (2009).
Spencer, S. L., Gaudet, S., Albeck, J. G., Burke, J. M. & Sorger, P. K. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459, 428–432 (2009).
Losick, R. & Desplan, C. Stochasticity and cell fate. Science 320, 65–68 (2008).
Sigal, A. et al. Variability and memory of protein levels in human cells. Nature 444, 643–646 (2006).
Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nat. Rev. Cancer 12, 323–334 (2012).
Brock, A., Chang, H. & Huang, S. Non-genetic heterogeneity—a mutation-independent driving force for the somatic evolution of tumours. Nat. Rev. Genet. 10, 336–342 (2009).
Huang, S., Ernberg, I. & Kauffman, S. Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective. Semin. Cell Dev. Biol. 20, 869–876 (2009).
Cohen, A. A. et al. Dynamic proteomics of individual cancer cells in response to a drug. Science 322, 1511–1516 (2008).
Huang, S. & Kauffman, S. How to escape the cancer attractor: rationale and limitations of multi-target drugs. Semin. Cancer Biol. 23, 270–278 (2013).
Shain, A. H. & Bastian, B. C. From melanocytes to melanomas. Nat. Rev. Cancer 16, 345–358 (2016).
Chen, H., Weng, Q. Y. & Fisher, D. E. UV signaling pathways within the skin. J. Invest. Dermatol. 134, 2080–2085 (2014).
Liu, J. J. & Fisher, D. E. Lighting a path to pigmentation: mechanisms of MITF induction by UV. Pigment Cell Melanoma Res. 23, 741–745 (2010).
King, R., Googe, P. B., Weilbaecher, K. N., Mihm, M. C. Jr & Fisher, D. E. Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors. Am. J. Surg. Pathol. 25, 51–57 (2001).
Yokoyama, S. et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480, 99–103 (2011).
Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).
Ugurel, S. et al. Microphthalmia-associated transcription factor gene amplification in metastatic melanoma is a prognostic marker for patient survival, but not a predictive marker for chemosensitivity and chemotherapy response. Clin. Cancer Res. 13, 6344–6350 (2007).
Jager, E. et al. Inverse relationship of melanocyte differentiation antigen expression in melanoma tissues and CD8+ cytotoxic-T cell responses: evidence for immunoselection of antigen-loss variants in vivo. Int. J. Cancer 66, 470–476 (1996).
Gogas, H. et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N. Engl. J. Med. 354, 709–718 (2006).
Freeman-Keller, M. et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin. Cancer Res. 22, 886–894 (2016).
Lo, J. A., Fisher, D. E. & Flaherty, K. T. Prognostic significance of cutaneous adverse events associated with pembrolizumab therapy. JAMA Oncol. 1, 1340–1341 (2015).
Fane, M. E. et al. NFIB mediates BRN2 driven melanoma cell migration and invasion through regulation of EZH2 and MITF. EBioMedicine 16, 63–75 (2017).
Kim, H. et al. Downregulation of the ubiquitin ligase RNF125 underlies resistance of melanoma cells to BRAF inhibitors via JAK1 deregulation. Cell Rep. 11, 1458–1473 (2015).
Slominski, A. et al. The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads to stimulation of HIF-1alpha expression and HIF-dependent attendant pathways. Arch. Biochem. Biophys. 563, 79–93 (2014).
Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell 174, 843–855 (2018).
Hartman, M. L. & Czyz, M. MITF in melanoma: mechanisms behind its expression and activity. Cell. Mol. Life Sci. 72, 1249–1260 (2015).
Koludrovic, D. & Davidson, I. MITF, the Janus transcription factor of melanoma. Future Oncol. 9, 235–244 (2013).
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
Rose, A. A. et al. MAPK pathway inhibitors sensitize BRAF-mutant melanoma to an antibody-drug conjugate targeting GPNMB. Clin. Cancer Res. 22, 6088–6098 (2016).
van Lanschot, C. G., Koljenovic, S., Grunhagen, D. J., Verhoef, C. & van Akkooi, A. C. Pigmentation in the sentinel node correlates with increased sentinel node tumor burden in melanoma patients. Melanoma Res. 24, 261–266 (2014).
Widmer, D. S. et al. Systematic classification of melanoma cells by phenotype-specific gene expression mapping. Pigment Cell Melanoma Res. 25, 343–353 (2012).
Altschuler, S. J. & Wu, L. F. Cellular heterogeneity: do differences make a difference? Cell 141, 559–563 (2010).
Bennett, D. C. Mechanisms of differentiation in melanoma cells and melanocytes. Environ. Health Perspect. 80, 49–59 (1989).
Konieczkowski, D. J. et al. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 4, 816–827 (2014).
Pearl Mizrahi, S., Gefen, O., Simon, I. & Balaban, N. Q. Persistence to anti-cancer treatments in the stationary to proliferating transition. Cell Cycle 15, 3442–3453 (2016).
Smith, M. P. et al. Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29, 270–284 (2016).
Muller, J. et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat. Commun. 5, 5712 (2014).
Song, C. et al. Recurrent tumor cell-intrinsic and -extrinsic alterations during MAPKi-induced melanoma regression and early adaptation. Cancer Discov. 7, 1248–1265 (2017).
Hensel, Z. et al. Stochastic expression dynamics of a transcription factor revealed by single-molecule noise analysis. Nat. Struct. Mol. Biol. 19, 797–802 (2012).
Hoek, K. S. et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res. 68, 650–656 (2008).
Kumar, D., Gorain, M., Kundu, G. & Kundu, G. C. Therapeutic implications of cellular and molecular biology of cancer stem cells in melanoma. Mol. Cancer 16, 7 (2017).
Brinckerhoff, C. E. Cancer stem cells (CSCs) in melanoma: there’s smoke, but is there fire? J. Cell. Physiol. 232, 2674–2678 (2017).
Murphy, G. F., Wilson, B. J., Girouard, S. D., Frank, N. Y. & Frank, M. H. Stem cells and targeted approaches to melanoma cure. Mol. Aspects Med. 39, 33–49 (2014).
Holzel, M., Bovier, A. & Tuting, T. Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat. Rev. Cancer 13, 365–376 (2013).
Pisco, A. O. & Huang, S. Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘what does not kill me strengthens me’. Br. J. Cancer 112, 1725–1732 (2015).
Litvin, O. et al. Interferon alpha/beta enhances the cytotoxic response of MEK inhibition in melanoma. Mol. Cell 57, 784–796 (2015).
Su, Y. et al. Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. Proc. Natl Acad. Sci. USA 114, 13679–13684 (2017).
Pisco, A. O. et al. Non-Darwinian dynamics in therapy-induced cancer drug resistance. Nat. Commun. 4, 2467 (2013).
Johannessen, C. M. et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504, 138–142 (2013).
Ji, Z. et al. MITF modulates therapeutic resistance through EGFR signaling. J. Invest. Dermatol. 135, 1863–1872 (2015).
Hata, A. N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016).
Ramirez, M. et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 7, 10690 (2016).
Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).
Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).
Kammertoens, T. et al. Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature 545, 98–102 (2017).
Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).
Ivashkiv, L. B. IFNgamma: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat. Rev. Immunol. 18, 545–558 (2018).
Minn, A. J. Interferons and the immunogenic effects of cancer therapy. Trends Immunol. 36, 725–737 (2015).
Shin, D. S. et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017).
Respa, A. et al. Association of IFN-gamma signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines. Clin. Cancer Res. 17, 2668–2678 (2011).
Sucker, A. et al. Genetic evolution of T cell resistance in the course of melanoma progression. Clin. Cancer Res. 20, 6593–6604 (2014).
White, C. A. et al. Constitutive transduction of peptide transporter and HLA genes restores antigen processing function and cytotoxic T cell-mediated immune recognition of human melanoma cells. Int. J. Cancer 75, 590–595 (1998).
Garcia-Diaz, A. et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19, 1189–1201 (2017).
Zaidi, M. R. et al. Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature 469, 548–553 (2011).
Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016).
Wischhusen, J., Waschbisch, A. & Wiendl, H. Immune-refractory cancers and their little helpers—an extended role for immunetolerogenic MHC molecules HLA-G and HLA-E? Semin. Cancer Biol. 17, 459–468 (2007).
Brocker, E. B., Zwadlo, G., Holzmann, B., Macher, E. & Sorg, C. Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int. J. Cancer 41, 562–567 (1988).
Rodriguez, T. et al. Patterns of constitutive and IFN-gamma inducible expression of HLA class II molecules in human melanoma cell lines. Immunogenetics 59, 123–133 (2007).
Mortarini, R., Belli, F., Parmiani, G. & Anichini, A. Cytokine-mediated modulation of HLA-class II, ICAM-1, LFA-3 and tumor-associated antigen profile of melanoma cells. Comparison with anti-proliferative activity by rIL1-beta, rTNF-alpha, rIFN-gamma, rIL4 and their combinations. Int. J. Cancer 45, 334–341 (1990).
Garbe, C. et al. Antitumor activities of interferon alpha, beta, and gamma and their combinations on human melanoma cells in vitro: changes of proliferation, melanin synthesis, and immunophenotype. J. Invest. Dermatol. 95 (Suppl. 6), 231–237 (1990).
Hemon, P. et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J. Immunol. 186, 5173–5183 (2011).
Mo, X. et al. Interferon-gamma signaling in melanocytes and melanoma cells regulates expression of CTLA-4. Cancer Res. 78, 436–450 (2018).
Spranger, S. et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl Med. 5, 200ra116 (2013).
Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl Med. 4, 127ra137 (2012).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Seo, S. K. et al. Attenuation of IFN-gamma-induced B7-H1 expression by 15-deoxy-delta(12,14)-prostaglandin J2 via downregulation of the Jak/STAT/IRF-1 signaling pathway. Life Sci. 112, 82–89 (2014).
Dong, H. et al. Tumor-associated B7-H1 promotes T cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
Minn, A. J. & Wherry, E. J. Combination cancer therapies with immune checkpoint blockade: convergence on interferon signaling. Cell 165, 272–275 (2016).
Brody, J. R. et al. Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8, 1930–1934 (2009).
Markel, G. et al. Dynamic expression of protective CEACAM1 on melanoma cells during specific immune attack. Immunology 126, 186–200 (2009).
Wang, T. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med. 10, 48–54 (2004).
Bahrambeigi, V. et al. PhiC31/PiggyBac modified stromal stem cells: effect of interferon gamma and/or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on murine melanoma. Mol. Cancer 13, 255 (2014).
Taniguchi, K. et al. Interferon gamma induces lung colonization by intravenously inoculated B16 melanoma cells in parallel with enhanced expression of class I major histocompatibility complex antigens. Proc. Natl Acad. Sci. USA 84, 3405–3409 (1987).
Brown, T. J., Lioubin, M. N. & Marquardt, H. Purification and characterization of cytostatic lymphokines produced by activated human T lymphocytes. Synergistic antiproliferative activity of transforming growth factor beta 1, interferon-gamma, and oncostatin M for human melanoma cells. J. Immunol. 139, 2977–2983 (1987).
Zaidi, M. R. & Merlino, G. The two faces of interferon-gamma in cancer. Clin. Cancer Res. 17, 6118–6124 (2011).
Matsushita, H. et al. Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFNgamma-dependent cell-cycle arrest. Cancer Immunol. Res. 3, 26–36 (2015).
Kortylewski, M. et al. Interferon-gamma-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals. J. Invest. Dermatol. 122, 414–422 (2004).
Schmitt, M. J. et al. Interferon-gamma-induced activation of signal transducer and activator of transcription 1 (STAT1) up-regulates the tumor suppressing microRNA-29 family in melanoma cells. Cell Commun. Signal 10, 41 (2012).
Raz, A. Actin organization, cell motility, and metastasis. Adv. Exp. Med. Biol. 233, 227–233 (1988).
Natarajan, V. T. et al. IFN-gamma signaling maintains skin pigmentation homeostasis through regulation of melanosome maturation. Proc. Natl Acad. Sci. USA 111, 2301–2306 (2014).
Gollob, J. A., Sciambi, C. J., Huang, Z. & Dressman, H. K. Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma. Cancer Res. 65, 8869–8877 (2005).
Le Poole, I. C. et al. Interferon-gamma reduces melanosomal antigen expression and recognition of melanoma cells by cytotoxic T cells. Am. J. Pathol. 160, 521–528 (2002).
Schultz, J. et al. Tumor-promoting role of signal transducer and activator of transcription (Stat)1 in late-stage melanoma growth. Clin. Exp. Metastasis 27, 133–140 (2010).
Ramsdale, R. et al. The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma. Sci. Signal 8, ra82 (2015).
Meyskens, F. L. Jr. et al. Randomized trial of adjuvant human interferon gamma versus observation in high-risk cutaneous melanoma: a Southwest Oncology Group study. J. Natl Cancer Inst. 87, 1710–1713 (1995).
Porter, G. A. et al. Significance of plasma cytokine levels in melanoma patients with histologically negative sentinel lymph nodes. Ann. Surg. Oncol. 8, 116–122 (2001).
He, Y. F. et al. Sustained low-level expression of interferon-gamma promotes tumor development: potential insights in tumor prevention and tumor immunotherapy. Cancer Immunol. Immunother. 54, 891–897 (2005).
Chhabra, Y. et al. Genetic variation in IRF4 expression modulates growth characteristics, tyrosinase expression and interferon-gamma response in melanocytic cells. Pigment Cell Melanoma Res. 31, 51–63 (2018).
Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).
Dunn, G. P. et al. Interferon-gamma and cancer immunoediting. Immunol. Res. 32, 231–245 (2005).
Kaplan, D. H. et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Natl Acad. Sci. USA 95, 7556–7561 (1998).
Kovarik, J. et al. Malignant melanoma associates with deficient IFN-induced STAT 1 phosphorylation. Int. J. Mol. Med. 12, 335–340 (2003).
Osborn, J. L. & Greer, S. F. Metastatic melanoma cells evade immune detection by silencing STAT1. Int. J. Mol. Sci. 16, 4343–4361 (2015).
Benci, J. L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554 (2016).
Zhao, C. et al. Feedback activation of STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol. Sci. 37, 47–61 (2016).
Li, Z. et al. Expression of SOCS-1, suppressor of cytokine signalling-1, in human melanoma. J. Invest. Dermatol. 123, 737–745 (2004).
Jager, E. et al. Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int. J. Cancer 71, 142–147 (1997).
Patel, S. J. et al. Identification of essential genes for cancer immunotherapy. Nature 548, 537–542 (2017).
Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418 (2017).
Restifo, N. P., Smyth, M. J. & Snyder, A. Acquired resistance to immunotherapy and future challenges. Nat. Rev. Cancer 16, 121–126 (2016).
Ribas, A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).
Bellone, M. & Elia, A. R. Constitutive and acquired mechanisms of resistance to immune checkpoint blockade in human cancer. Cytokine Growth Factor Rev. 36, 17–24 (2017).
Gao, J. et al. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397–404 (2016).
Chang, C. C. et al. Multiple structural and epigenetic defects in the human leukocyte antigen class I antigen presentation pathway in a recurrent metastatic melanoma following immunotherapy. J. Biol. Chem. 290, 26562–26575 (2015).
Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 (2017).
Pardoll, D. Cancer and the immune system: basic concepts and targets for intervention. Semin. Oncol. 42, 523–538 (2015).
Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).
Overacre-Delgoffe, A. E. et al. Interferon-gamma drives treg fragility to promote anti-tumor immunity. Cell 169, 1130–1141 (2017).
Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).
Zhao, X. & Subramanian, S. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res. 77, 817–822 (2017).
Herlyn, M., Guerry, D. & Koprowski, H. Recombinant gamma-interferon induces changes in expression and shedding of antigens associated with normal human melanocytes, nevus cells, and primary and metastatic melanoma cells. J. Immunol. 134, 4226–4230 (1985).
Reinhardt, J. et al. MAPK signaling and inflammation link melanoma phenotype switching to induction of CD73 during immunotherapy. Cancer Res. 77, 4697–4709 (2017).
Landsberg, J. et al. Melanomas resist T cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012).
Braumuller, H. et al. T-Helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013).
Zingg, D. et al. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep. 20, 854–867 (2017).
Riesenberg, S. et al. MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment. Nat. Commun. 6, 8755 (2015).
Sanchez-Perez, L. et al. Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo. Cancer Res. 65, 2009–2017 (2005).
Falletta, P. et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev. 31, 18–33 (2017).
Haferkamp, S. et al. Vemurafenib induces senescence features in melanoma cells. J. Invest. Dermatol. 133, 1601–1609 (2013).
Webster, M. R. et al. Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells. Pigment Cell Melanoma Res. 28, 184–195 (2015).
Tsao, H., Fukunaga-Kalabis, M. & Herlyn, M. Recent advances in melanoma and melanocyte biology. J. Invest. Dermatol. 137, 557–560 (2017).
Giuliano, S. et al. Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas. Cancer Res. 70, 3813–3822 (2010).
Shaffer, S. M. et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546, 431–435 (2017).
Mo, J. et al. Hypoxia-induced senescence contributes to the regulation of microenvironment in melanomas. Pathol. Res. Pract. 209, 640–647 (2013).
La Porta, C. A., Zapperi, S. & Sethna, J. P. Senescent cells in growing tumors: population dynamics and cancer stem cells. PLOS Comput. Biol. 8, e1002316 (2012).
Giampietri, C. et al. Cancer microenvironment and endoplasmic reticulum stress response. Mediators Inflamm. 2015, 417281 (2015).
Li, Y. & Laterra, J. Cancer stem cells: distinct entities or dynamically regulated phenotypes? Cancer Res. 72, 576–580 (2012).
Zhang, X. et al. Both complexity and location of DNA damage contribute to cellular senescence induced by ionizing radiation. PLOS ONE 11, e0155725 (2016).
Collado, M. & Serrano, M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer 10, 51–57 (2010).
Sun, X. et al. Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway. Cell Death Dis. 9, 260 (2018).
Liu, Y. et al. Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-kappaB impairs this drug-induced senescence. EMBO Mol. Med. 5, 149–166 (2013).
Gray-Schopfer, V. C., Karasarides, M., Hayward, R. & Marais, R. Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. Cancer Res. 67, 122–129 (2007).
Obenauf, A. C. et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 520, 368–372 (2015).
Ohanna, M. et al. Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype. Oncotarget 4, 2212–2224 (2013).
Somasundaram, R. et al. Tumor-associated B cells induce tumor heterogeneity and therapy resistance. Nat. Commun. 8, 607 (2017).
Hsu, M. Y. et al. Notch3 signaling-mediated melanoma-endothelial crosstalk regulates melanoma stem-like cell homeostasis and niche morphogenesis. Lab Invest. 97, 725–736 (2017).
Wang, T. et al. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin. Cancer Res. 21, 1652–1664 (2015).
Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27, 574–588 (2015).
Flach, E. H., Rebecca, V. W., Herlyn, M., Smalley, K. S. & Anderson, A. R. Fibroblasts contribute to melanoma tumor growth and drug resistance. Mol. Pharm. 8, 2039–2049 (2011).
Fedorenko, I. V., Wargo, J. A., Flaherty, K. T., Messina, J. L. & Smalley, K. S. M. BRAF inhibition generates a host-tumor niche that mediates therapeutic escape. J. Invest. Dermatol. 135, 3115–3124 (2015).
Young, H. L. et al. An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition. J. Exp. Med. 214, 1691–1710 (2017).
Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).
Ohanna, M. et al. Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS). Genes Dev. 25, 1245–1261 (2011).
Jobe, N. P. et al. Simultaneous blocking of IL-6 and IL-8 is sufficient to fully inhibit CAF-induced human melanoma cell invasiveness. Histochem. Cell Biol. 146, 205–217 (2016).
Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).
Smith, M. P. et al. Effect of SMURF2 targeting on susceptibility to MEK inhibitors in melanoma. J. Natl Cancer Inst. 105, 33–46 (2013).
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
Sharma, R. et al. Activity-based protein profiling shows heterogeneous signaling adaptations to BRAF inhibition. J. Proteome Res. 15, 4476–4489 (2016).
Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
Titz, B. et al. JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma. Cell Discov. 2, 16028 (2016).
Sun, C. et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508, 118–122 (2014).
Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949 (2017).
Mak, M. P. et al. A patient-derived, pan-cancer EMT signature identifies global molecular alterations and immune target enrichment following epithelial-to-mesenchymal transition. Clin. Cancer Res. 22, 609–620 (2016).
Maccalli, C., Parmiani, G. & Ferrone, S. Immunomodulating and immunoresistance properties of cancer-initiating cells: implications for the clinical success of immunotherapy. Immunol. Invest. 46, 221–238 (2017).
Schachter, J. et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390, 1853–1862 (2017).
Long, G. V. et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann. Oncol. 28, 1631–1639 (2017).
Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013).
Kong, X. et al. Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature 550, 270–274 (2017).
Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).
Valpione, S. et al. Rechallenge with BRAF-directed treatment in metastatic melanoma: a multi-institutional retrospective study. Eur. J. Cancer 91, 116–124 (2018).
De Luca, A. et al. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget 6, 14777–14795 (2015).
Duellman, S. J. et al. A novel steroidal inhibitor of estrogen-related receptor alpha (ERR alpha). Biochem. Pharmacol. 80, 819–826 (2010).
Bardini, M. et al. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement. Leukemia 29, 38–50 (2015).
Keats, J. J. et al. Clonal competition with alternating dominance in multiple myeloma. Blood 120, 1067–1076 (2012).
Charles, J. P. et al. Monitoring the dynamics of clonal tumour evolution in vivo using secreted luciferases. Nat. Commun. 5, 3981 (2014).
Cleary, A. S., Leonard, T. L., Gestl, S. A. & Gunther, E. J. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 508, 113–117 (2014).
Miller, D. M. & Flaherty, K. T. Cyclin-dependent kinases as therapeutic targets in melanoma. Pigment Cell Melanoma Res. 27, 351–365 (2014).
Wan, L., Pantel, K. & Kang, Y. Tumor metastasis: moving new biological insights into the clinic. Nat. Med. 19, 1450–1464 (2013).
Roesch, A. et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell 23, 811–825 (2013).
Kirkwood, J. M. et al. Effect of JAK/STAT or PI3Kδ plus PD-1 inhibition on the tumor microenvironment: biomarker results from a phase Ib study in patients with advanced solid tumors [abstract]. Cancer Res. 78 (Suppl. 13), CT176 (2018).
Winkler, J. K., Schiller, M., Bender, C., Enk, A. H. & Hassel, J. C. Rituximab as a therapeutic option for patients with advanced melanoma. Cancer Immunol. Immunother. 67, 917–924 (2018).
Lauss, M. et al. Genome-wide DNA methylation analysis in melanoma reveals the importance of CpG methylation in MITF regulation. J. Invest. Dermatol. 135, 1820–1828 (2015).
Chatterjee-Kishore, M., Kishore, R., Hicklin, D. J., Marincola, F. M. & Ferrone, S. Different requirements for signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 in the regulation of low molecular mass polypeptide 2 and transporter associated with antigen processing 1 gene expression. J. Biol. Chem. 273, 16177–16183 (1998).
Gowrishankar, K. et al. Inducible but not constitutive expression of PD-L1 in human melanoma cells is dependent on activation of NF-κB. PLOS ONE 10, e0123410 (2015).
Platanias, L. C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005).
Lee, H. et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat. Med. 16, 1421–1428 (2010).
Kreis, S., Munz, G. A., Haan, S., Heinrich, P. C. & Behrmann, I. Cell density dependent increase of constitutive signal transducers and activators of transcription 3 activity in melanoma cells is mediated by Janus kinases. Mol. Cancer Res. 5, 1331–1341 (2007).
Nam, S. Novel synthetic derivatives of the natural product berbamine inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells. Mol. Oncol. 6, 484–493 (2012).
Sims, J. T. et al. Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS ONE 8, e55509 (2013).
Lee, H. et al. A requirement of STAT3 DNA binding precludes Th-1 immunostimulatory gene expression by NF-κB in tumors. Cancer Res. 71, 3772–3780 (2011).
Lee, H. et al. Persistently activated Stat3 maintains constitutive NF-κB activity in tumors. Cancer Cell 15, 283–293 (2009).
Zhang, L. et al. Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo and via disrupting proinflammatory cytokines-mediated NF-κB and STAT3 pathways. IUBMB Life 67, 778–788 (2015).
Wong, L. H., Hatzinisiriou, I., Devenish, R. J. & Ralph, S. J. IFN-γ priming up-regulates IFN-stimulated gene factor 3 (ISGF3) components, augmenting responsiveness of IFN-resistant melanoma cells to type I IFNs. J. Immunol. 160, 5475–5484 (1998).
Kovarik A. et al. Interferon-gamma, but not interferon-alpha, induces SOCS 3 expression in human melanoma cell lines. Melanoma Res. 15, 481–488 (2005).
Lesinski, G. B. et al. Modulation of SOCS protein expression influences the interferon responsiveness of human melanoma cells. BMC Cancer 10, 142 (2010).
Huang, F.-J. et al. Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis. Cancer Res. 68, 9634–9642 (2008).
Murtas, D. et al. IRF-1 responsiveness to IFN-γ predicts different cancer immune phenotypes. Br. J. Cancer 109, 76–82 (2013).
Acknowledgements
D.E.F. acknowledges grant support from the NIH (5P01 CA163222 and 2R01 AR043369) and the Dr Miriam and Sheldon G. Adelson Medical Research Foundation. K.T.F. acknowledges grant support from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation.
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D.E.F. has a financial interest associated with Soltego, which was reviewed and is currently managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. K.T.F. serves on the Board of Directors of Clovis Oncology, Loxo Oncology, Strata Oncology and Vivid Biosciences; serves on the Corporate Advisory Boards of PIC Therapeutics and X4 Pharmaceuticals; serves on the Scientific Advisory Boards of Adaptimmune, Aeglea, Amgen, Apricity, Arch Oncology, Array BioPharma, Asana, Fog Pharma, Fount, Neon Therapeutics, Oncoceutics, Sanofi, Shattuck Labs, Tolero and Tvardi; and is a consultant to Bristol-Myers Squibb, Boston Biomedical, Cell Medica, Checkmate, Debiopharm, Genentech, Merck, Novartis, Pierre Fabre, Takeda and Verastem. X.B. declares no competing interests.
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Bai, X., Fisher, D.E. & Flaherty, K.T. Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways. Nat Rev Clin Oncol 16, 549–562 (2019). https://doi.org/10.1038/s41571-019-0204-6
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DOI: https://doi.org/10.1038/s41571-019-0204-6
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