- Email: [email protected]
The Taming of the TAMs
TICB 1259 No. of Pages 2
Spotlight
The Taming of the TAMs Joan Seoane1,2,* Tumor-associated macrophages and microglia (TAMs) are considered crucial elements in cancer progression. Recent work reveals the molecular mechanisms underlying acquired resistance to colony-stimulating factor-1 receptor (CSF-1R) inhibitors in glioblastoma (GBM) and shows that targeting TAMs with CSF-1R inhibitors leads to an antitumor response in GBM followed by the acquisition of resistance to treatment through the induction of insulin-like growth factor 1 (IGF-1) expression in TAMs. One of the most important challenges in the treatment of cancer is its evolving intratumor heterogeneity. Tumors such as GBM comprise mosaics of cells that fluctuate with time. Cancer can be viewed, then, as an evolving ecosystem following Darwinian selection. Therapeutic treatments dictate the evolution of cell populations within the tumor in concordance with the ‘survival of the fittest’ aspect of Darwinian evolution. This concept has critical biological and clinical implications since the selection of the fittest population of cells will generate resistance to therapies. Moreover, as in the case of ecosystems of living organisms, the evolving diversity of tumor cells interacts and adapts to their niche generating a dependency between the tumor and its microenvironment. This dependency can be therapeutically exploited since tackling the niche instead of the tumor might circumvent the challenge of treating an evolving, heterogeneous target. Work over recent years is beginning to shed light on the intense crosstalk
between tumor cells and their microenvironment. The deep understanding of the molecular interactions in the tumor niche is facilitating the identification of novel therapeutic targets and the design of effective anticancer compounds. Within the tumor microenvironment, TAMs are considered critical elements in cancer progression [1]. TAMs are highly infiltrated in some tumor types, such as GBM, and have been shown to promote tumor growth and progression through the induction of tumor cell proliferation and invasion, angiogenesis, and local immunosuppression [2–4]. This has led to the development of several pharmacological compounds that target TAMs. By targeting genetically stable TAMs, the complex and fluctuating intratumor heterogeneity can be bypassed and the chances of acquired resistance may decrease. In a recent study in Science [5], Quail et al. aim to understand the molecular mechanisms involved in the acquired resistance to TAM-directed treatments. Specifically, the study focuses on the antitumor effect of CSF-1R inhibitors in the context of GBM. In previous work [6], a thorough preclinical study of CSF-1R inhibitors in mouse models of GBM demonstrated that these inhibitors can be promising agents against tumors. The inhibition of CSF-1R showed a strong anticancer response that was mediated by the polarization of TAMs, preventing their tumor-promoting functions. Importantly, clinical trials are in progress using inhibitors of CSF-1R in several tumor types including GBM. Although the longterm effects of the CSF-1R trials remain under evaluation [7], Quail et al. moved one step ahead and gained insights into potential mechanisms of drug resistance. They first performed a long-term preclinical trial to assess whether resistance to treatment developed over time. Most of the CSF-1R inhibitor-treated tumors regressed and then entered a dormancy phase. Interestingly, in more than half of the treated animals tumors rebounded after dormancy despite continuous treatment with the
CSF-1R inhibitor [5], which indicated that a large proportion of dormant tumors acquired resistance to treatment. The authors next studied the molecular mechanisms underlying resistance to treatment and analyzed samples of untreated, regressing, dormant, and rebounding tumors. They found that the PI3K pathway was systematically elevated in resistant tumors and combinatory treatments with CSF-1R and PI3K inhibitors partially prevented the rebound of tumors. Importantly, the resistant phenotype was induced by the tumor microenvironment, since the transplantation of cells from rebound tumors into a secondary mouse resensitized the tumor to CSF-1R inhibitors. Among the diverse elements of the tumor microenvironment, TAMs were found to be responsible for the acquisition of the resistant phenotype by the tumor cells. IL4, likely produced by T cells, polarized TAMs and made them express numerous factors involved in wound healing and resolving inflammation. Among these factors, IGF-1 was identified as the factor responsible for the increased PI3K pathway found in CSF-1R-resistant tumor cells. Through the activation of the transcription factors NFAT and STAT6, IL4 induced the expression of IGF-1 in TAMs, which signaled through neighboring tumor cells, activating the PI3K pathway to promote cell proliferation and tumor rebound. Combinations of IGF-1, NFAT, or STAT6 inhibitors with CSF-1R inhibitors partially prevented tumor recurrence (Figure 1). The work by Quail et al. shows a fascinating interplay between TAMs and tumor cells that evolves during treatment to adapt and escape CSF-1R inhibition. Although TAMs are genetically more stable than tumor cells, TAMs still maintain the versatility to change and facilitate the growth of tumors. Following the parallelism with ecosystems, cancer does not act as an ‘organism’ in isolation but evolves in intimate contact with its microenvironment to subsist in changing conditions. In a way, tumor cells ‘tame’ TAMs to resist
Trends in Cell Biology, Month Year, Vol. xx, No. yy
1
TICB 1259 No. of Pages 2
IGF-1 CSF-1R inhibitor CSF-1 PI3K NFAT STAT6
1 Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, c/Natzaret, 115-117, 08035 Barcelona, Spain 2 Institució Catalana de Recerca i Estudis Avançats
TAM IL4
Quail and coworkers are advancing the results of clinical trials to prepare for potential resistance to CSF-1R inhibitors and to then act accordingly. We must now wait for the clinical outcome in patients to validate their results and, based on the described findings, be ready to counteract the versatile and evolving tumor-niche ecosystem through rational and effective combinatory treatments.
(ICREA), 08010 Barcelona, Spain
Rebounding tumor cell *Correspondence: [email protected] (J. Seoane). http://dx.doi.org/10.1016/j.tcb.2016.06.007
Figure 1. Long-Term Treatment with Colony-Stimulating Factor-1 Receptor (CSF-1R) Inhibitors Promotes Tumor Resistance. After responding to CSF-1R inhibitors, the remaining dormant tumor cells rebound and start proliferating due to the insulin-like growth factor 1 (IGF-1)-mediated induction of the PI3K pathway. IGF-1 is produced by tumor-associated macrophages and microglia (TAMs) in response to the IL4– NFAT/STAT6 pathway.
the selective pressure of anticancer new questions. Why and how does IL4 suddenly appear in[2_TD$IF] just half[3_TD$IF] (and not treatments. all) of the dormant tumors to drive resisThe work is performed using animal tance? How will the standard of care models and hence the translation of ([4_TD$IF]radiotherapy- and chemotherapy) with some of the results into human reality which patients are treated affect these procould be limited. We know that human cesses? Most GBM patients exhibit a tumors are more complex and heteroge- hyperactive PI3K pathway due to either neous than those in mice. In addition, we PTEN alterations or PIK3CA mutations still do not know how the specific geno- [8][5_TD$IF] –[6_TD$IF] will this impact the CSF-1R response? mic makeup of each human GBM will The answers to these questions will faciliimpact the response or resistance to tate quick translation of the findings of anti-CSF-1R. [1_TD$IF]Moreover, this work raises Quail et al. to the benefit of patients.
2
Trends in Cell Biology, Month Year, Vol. xx, No. yy
References 1. Klemm, F. and Joyce, J.A. (2015) Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 25, 198–213 2. Biswas, S.K. and Mantovani, A. (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 3. Noy, R. and Pollard, J.W. (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 4. Ruffell, B. and Coussens, L.M. (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 5. Quail, D.F. et al. (2016) The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 6. Pyonteck, S.M. et al. (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 7. Butowski, N. et al. (2016) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium Phase II study. Neuro Oncol. 18, 557–564 8. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068
Spotlight
The Taming of the TAMs Joan Seoane1,2,* Tumor-associated macrophages and microglia (TAMs) are considered crucial elements in cancer progression. Recent work reveals the molecular mechanisms underlying acquired resistance to colony-stimulating factor-1 receptor (CSF-1R) inhibitors in glioblastoma (GBM) and shows that targeting TAMs with CSF-1R inhibitors leads to an antitumor response in GBM followed by the acquisition of resistance to treatment through the induction of insulin-like growth factor 1 (IGF-1) expression in TAMs. One of the most important challenges in the treatment of cancer is its evolving intratumor heterogeneity. Tumors such as GBM comprise mosaics of cells that fluctuate with time. Cancer can be viewed, then, as an evolving ecosystem following Darwinian selection. Therapeutic treatments dictate the evolution of cell populations within the tumor in concordance with the ‘survival of the fittest’ aspect of Darwinian evolution. This concept has critical biological and clinical implications since the selection of the fittest population of cells will generate resistance to therapies. Moreover, as in the case of ecosystems of living organisms, the evolving diversity of tumor cells interacts and adapts to their niche generating a dependency between the tumor and its microenvironment. This dependency can be therapeutically exploited since tackling the niche instead of the tumor might circumvent the challenge of treating an evolving, heterogeneous target. Work over recent years is beginning to shed light on the intense crosstalk
between tumor cells and their microenvironment. The deep understanding of the molecular interactions in the tumor niche is facilitating the identification of novel therapeutic targets and the design of effective anticancer compounds. Within the tumor microenvironment, TAMs are considered critical elements in cancer progression [1]. TAMs are highly infiltrated in some tumor types, such as GBM, and have been shown to promote tumor growth and progression through the induction of tumor cell proliferation and invasion, angiogenesis, and local immunosuppression [2–4]. This has led to the development of several pharmacological compounds that target TAMs. By targeting genetically stable TAMs, the complex and fluctuating intratumor heterogeneity can be bypassed and the chances of acquired resistance may decrease. In a recent study in Science [5], Quail et al. aim to understand the molecular mechanisms involved in the acquired resistance to TAM-directed treatments. Specifically, the study focuses on the antitumor effect of CSF-1R inhibitors in the context of GBM. In previous work [6], a thorough preclinical study of CSF-1R inhibitors in mouse models of GBM demonstrated that these inhibitors can be promising agents against tumors. The inhibition of CSF-1R showed a strong anticancer response that was mediated by the polarization of TAMs, preventing their tumor-promoting functions. Importantly, clinical trials are in progress using inhibitors of CSF-1R in several tumor types including GBM. Although the longterm effects of the CSF-1R trials remain under evaluation [7], Quail et al. moved one step ahead and gained insights into potential mechanisms of drug resistance. They first performed a long-term preclinical trial to assess whether resistance to treatment developed over time. Most of the CSF-1R inhibitor-treated tumors regressed and then entered a dormancy phase. Interestingly, in more than half of the treated animals tumors rebounded after dormancy despite continuous treatment with the
CSF-1R inhibitor [5], which indicated that a large proportion of dormant tumors acquired resistance to treatment. The authors next studied the molecular mechanisms underlying resistance to treatment and analyzed samples of untreated, regressing, dormant, and rebounding tumors. They found that the PI3K pathway was systematically elevated in resistant tumors and combinatory treatments with CSF-1R and PI3K inhibitors partially prevented the rebound of tumors. Importantly, the resistant phenotype was induced by the tumor microenvironment, since the transplantation of cells from rebound tumors into a secondary mouse resensitized the tumor to CSF-1R inhibitors. Among the diverse elements of the tumor microenvironment, TAMs were found to be responsible for the acquisition of the resistant phenotype by the tumor cells. IL4, likely produced by T cells, polarized TAMs and made them express numerous factors involved in wound healing and resolving inflammation. Among these factors, IGF-1 was identified as the factor responsible for the increased PI3K pathway found in CSF-1R-resistant tumor cells. Through the activation of the transcription factors NFAT and STAT6, IL4 induced the expression of IGF-1 in TAMs, which signaled through neighboring tumor cells, activating the PI3K pathway to promote cell proliferation and tumor rebound. Combinations of IGF-1, NFAT, or STAT6 inhibitors with CSF-1R inhibitors partially prevented tumor recurrence (Figure 1). The work by Quail et al. shows a fascinating interplay between TAMs and tumor cells that evolves during treatment to adapt and escape CSF-1R inhibition. Although TAMs are genetically more stable than tumor cells, TAMs still maintain the versatility to change and facilitate the growth of tumors. Following the parallelism with ecosystems, cancer does not act as an ‘organism’ in isolation but evolves in intimate contact with its microenvironment to subsist in changing conditions. In a way, tumor cells ‘tame’ TAMs to resist
Trends in Cell Biology, Month Year, Vol. xx, No. yy
1
TICB 1259 No. of Pages 2
IGF-1 CSF-1R inhibitor CSF-1 PI3K NFAT STAT6
1 Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, c/Natzaret, 115-117, 08035 Barcelona, Spain 2 Institució Catalana de Recerca i Estudis Avançats
TAM IL4
Quail and coworkers are advancing the results of clinical trials to prepare for potential resistance to CSF-1R inhibitors and to then act accordingly. We must now wait for the clinical outcome in patients to validate their results and, based on the described findings, be ready to counteract the versatile and evolving tumor-niche ecosystem through rational and effective combinatory treatments.
(ICREA), 08010 Barcelona, Spain
Rebounding tumor cell *Correspondence: [email protected] (J. Seoane). http://dx.doi.org/10.1016/j.tcb.2016.06.007
Figure 1. Long-Term Treatment with Colony-Stimulating Factor-1 Receptor (CSF-1R) Inhibitors Promotes Tumor Resistance. After responding to CSF-1R inhibitors, the remaining dormant tumor cells rebound and start proliferating due to the insulin-like growth factor 1 (IGF-1)-mediated induction of the PI3K pathway. IGF-1 is produced by tumor-associated macrophages and microglia (TAMs) in response to the IL4– NFAT/STAT6 pathway.
the selective pressure of anticancer new questions. Why and how does IL4 suddenly appear in[2_TD$IF] just half[3_TD$IF] (and not treatments. all) of the dormant tumors to drive resisThe work is performed using animal tance? How will the standard of care models and hence the translation of ([4_TD$IF]radiotherapy- and chemotherapy) with some of the results into human reality which patients are treated affect these procould be limited. We know that human cesses? Most GBM patients exhibit a tumors are more complex and heteroge- hyperactive PI3K pathway due to either neous than those in mice. In addition, we PTEN alterations or PIK3CA mutations still do not know how the specific geno- [8][5_TD$IF] –[6_TD$IF] will this impact the CSF-1R response? mic makeup of each human GBM will The answers to these questions will faciliimpact the response or resistance to tate quick translation of the findings of anti-CSF-1R. [1_TD$IF]Moreover, this work raises Quail et al. to the benefit of patients.
2
Trends in Cell Biology, Month Year, Vol. xx, No. yy
References 1. Klemm, F. and Joyce, J.A. (2015) Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 25, 198–213 2. Biswas, S.K. and Mantovani, A. (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 3. Noy, R. and Pollard, J.W. (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 4. Ruffell, B. and Coussens, L.M. (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 5. Quail, D.F. et al. (2016) The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 6. Pyonteck, S.M. et al. (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 7. Butowski, N. et al. (2016) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium Phase II study. Neuro Oncol. 18, 557–564 8. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068