- Email: [email protected]
Senescence and Cancer: In the Name of Immunosuppression
Cancer Cell
Previews and should facilitate a more in-depth analysis of SOX2 function in the context of 3q26-driven LSCC.
Hammerman, P.S., Lawrence, M.S., Voet, D., Jing, R., Cibulskis, K., Sivachenko, A., Stojanov, P., McKenna, A., Lander, E.S., Gabriel, S., et al.; Cancer Genome Atlas Research Network (2012). Nature 489, 519–525.
REFERENCES
Hayes, S.A., Hudson, A.L., Clarke, S.J., Molloy, M.P., and Howell, V.M. (2014). Semin. Cell Dev. Biol. 27, 118–127.
Ferone, G., Song, Y.J., Sutherland, K.D., Bhaskaran, R., Monkhorst, K., Lambooij, J.P., Proost, N., Gargiulo, G., and Berns, A. (2016). Cancer Cell 30, this issue, 519–532. Fields, A.P., Justilien, V., and Murray, N.R. (2016). Adv. Biol. Regul. 60, 47–63.
Justilien, V., and Fields, A.P. (2009). Oncogene 28, 3597–3607. Justilien, V., Walsh, M.P., Ali, S.A., Thompson, E.A., Murray, N.R., and Fields, A.P. (2014). Cancer Cell 25, 139–151.
Mukhopadhyay, A., Berrett, K.C., Kc, U., Clair, P.M., Pop, S.M., Carr, S.R., Witt, B.L., and Oliver, T.G. (2014). Cell Rep. 8, 40–49. Siegel, R.L., Miller, K.D., and Jemal, A. (2016). CA Cancer J. Clin. 66, 7–30. Wang, Y., Zhang, Z., Yan, Y., Lemon, W.J., LaRegina, M., Morrison, C., Lubet, R., and You, M. (2004). Cancer Res. 64, 1647–1654. Xu, C., Fillmore, C.M., Koyama, S., Wu, H., Zhao, Y., Chen, Z., Herter-Sprie, G.S., Akbay, E.A., Tchaicha, J.H., Altabef, A., et al. (2014). Cancer Cell 25, 590–604.
Senescence and Cancer: In the Name of Immunosuppression Susana Llanos1,* and Manuel Serrano1,* 1Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain *Correspondence: [email protected] (S.L.), [email protected] (M.S.) http://dx.doi.org/10.1016/j.ccell.2016.09.015
Senescent cells and cancer cells recruit immunosuppressive myeloid cells. In this issue of Cancer Cell, Eggert et al. report that senescent cells recruit immature myeloid cells (iMCs) through the secretion of the CCL2 cytokine and that these iMCs have pro- or anti-tumorigenic activities, depending on the cellular context.
Cellular senescence is a stress response that restricts the proliferation of damaged cells and thus plays an important role in tumor suppression. A significant feature of senescent cells is the secretion of many proteins, including immune-attracting cytokines and chemokines, growth factors, and matrix remodeling proteases, collectively known as the senescenceassociated secretory phenotype (SASP). A prominent consequence of the SASP is the recruitment of immune cells; however, these immune cells have paradoxically antagonistic effects on cancer. On one hand, T cells, macrophages, and natural killer cells mediate the removal of senescent cells. This process, known as senescence surveillance or clearance, contributes to prevent tumor initiation (Kang et al., 2011) and also participates in the regression of cancers that have undergone p53-mediated senescence (Xue et al., 2007). On the other hand, senescent cells recruit immunosuppressive myeloid cells that create an immunotolerant context that allows tumor growth (Luo
et al., 2016; Ruhland et al., 2016; Toso et al., 2014). Immunosuppressive myeloid cells are generally defined by the surface markers CD11b and Gr1 (CD11b+Gr1+). In the absence of tumor-derived factors, CD11b+Gr1+ cells retain the ability to differentiate into dendritic cells, macrophages, or neutrophils, and thereby are referred to as immature myeloid cells (iMCs). However, in the presence of tumor-derived factors, CD11b+Gr1+ cells lose their capacity to differentiate and inhibit the function of other immune cells, namely T cells, dendritic cells, macrophages, and natural killer (NK) cells, thereby creating an immunotolerant environment that allows tumor progression. These tumor-associated CD11b+Gr1+ cells are generally known as myeloidderived suppressive cells (MDSCs) (Talmadge and Gabrilovich, 2013). It remains to be defined to what extent CD11b+Gr1+ cells in a non-tumoral context (i.e., iMCs) are different from CD11b+Gr1+ cells in a tumoral context (i.e., MDSCs).
In the current issue of Cancer Cell, Eggert et al. report that senescence-recruited CD11b+Gr1+ cells can be anti- or pro-tumorigenic, depending on the cellular context (Eggert et al., 2016). The current study is based on a mouse model of oncogene-induced senescence (OIS) by intrahepatic delivery of oncogenic NrasG12V. In this biological setting, clearance of senescent hepatocytes prevents neoplastic progression (Kang et al., 2011). Eggert and colleges demonstrate that the production of the cytokine CCL2 (also known as MCP-1) by senescent cells plays a key role in the recruitment of immature CD11b+Gr1+ cells that subsequently mature into macrophages. The authors observe that these macrophages are relevant (1) for the establishment and reinforcement of senescence through the production of immune-secreted factors in a feed-forward loop and (2) for the clearing of senescent cells (Figure 1). Accordingly, mice deficient for the CCL2 receptor CCR2 are highly susceptible to the development of hepatocellular
Cancer Cell 30, October 10, 2016 ª 2016 Elsevier Inc. 507
Cancer Cell
Previews ANTI-TUMORAL
CD11b+Gr1+ myeloid cells
PRO-TUMORAL
maturation
CCL2
Tumor cells
Senescent cells
Macrophages Figure 1. Crosstalk between Senescent Cells and Cancer Cells Dictates the Anti- or Protumorigenic Activity of Immature Myeloid Cells In the absence of tumor cells, senescence-recruited CD11b+Gr1+ myeloid cells differentiate into macrophages that mediate senescence clearance and tumor protection. In the presence of tumor-secreted factors, CD11b+Gr1+ cells fail to differentiate and their immunosuppressive activities allow neoplastic cells to evade the immune system and promote tumor growth.
carcinomas (HCCs) upon introduction of NrasG12V. Interestingly, however, cancer cells can subvert to their advantage the activity of the myeloid cells recruited by senescent cells. Eggert and colleagues observe that when hepatocellular tumor cells infiltrate livers containing senescent cells, myeloid cells accumulate and create a potent immunotolerant environment rather than maturing into macrophages. This concept is in agreement with previous publications reporting that senescent cells promote cancer growth through the recruitment of immunosuppressive CD11b+Gr1+ cells (Luo et al., 2016; Ruhland et al., 2016; Toso et al., 2014). Based on their findings in a non-tumoral context, Eggert and colleagues demonstrate that senescent cells also recruit CD11b+Gr1+ cells through the CCL2-CCR2 axis in the presence of tumor cells. In this case, however, HCC cells hinder the differentiation of immature CD11b+Gr1+ cells into macrophages (Figure 1). Importantly, these tumor-educated CD11b+Gr1+ cells are now blocked in an immunosuppressive state that favors tumor growth. Also, the absence of macrophage differentiation allows the accumulation of senescent cells, which further amplifies the recruitment of CD11b+Gr1+ cells via CCL2. Supporting these observations, Eggert 508 Cancer Cell 30, October 10, 2016
et al. report that in HCC patients, peritumoral senescence is associated with increased CCL2 expression, infiltration of immunosuppressive cells, reduced NK cells, and poorer prognosis. These observations have therapeutic implications. The most immediate one is that pharmacologically interfering with the SASP or its targets (for example, using CCR2 antagonists) may benefit HCC patients by reducing the recruitment of immunosuppressive cells. However, as pointed out by the authors, this type of intervention may promote tumor growth in patients at risk of developing liver cancer, such as those with chronic liver damage. The work by Eggert and colleges also suggests that in situations in which senescence and tumor cells coexist, as in the case of chemotherapy-treated tumors, interfering with the secretome of tumor cells may reactivate the differentiation of CD11b+Gr1+ cells into macrophages, thereby disrupting immunotolerance and triggering the elimination of both tumor cells and chemotherapyinduced senescent cells. In this regard, it would be important to identify the key tumor-secreted factors that prevent the differentiation of CD11b+Gr1+ cells into macrophages. In addition, this work poses new questions about how tumor cells crosstalk to senescent cells. It is
conceivable that, besides interacting with immune cells, the tumor secretome may directly modulate the function of senescent cells or the senescent secretory phenotype. Finally, one interesting implication of this study is that, in the absence of a cancer environment, senescence-recruited CD11b+Gr1+ cells may have beneficial implications beyond protection from cancer initiation. In particular, senescent cells accumulate in many human pathologies and during aging, and are responsible, at least in part, for the loss of tissue function (Mun˜oz-Espı´n and Serrano, 2014). Interestingly, it has been reported that CD11b+Gr1+ cells increase in the blood and lymphoid organs during aging (Enioutina et al., 2011). These elevated levels of CD11b+Gr1+ cells can now be explained as a consequence of the accumulation of senescent cells during aging. Conceivably, CD11b+Gr1+ cells may elicit the disposal of agingassociated senescent cells thereby reducing tissue dysfunction during aging. In relation to this, potentiating the activity of CD11b+Gr1+ cells may have beneficial and therapeutic effects on aging and on multiple senescence-associated diseases. REFERENCES Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Median-Echeverz, J., Longerich, T., Forges, M., Reinsinger, F., et al. (2016). Cancer Cell 30, this issue, 533–547. Enioutina, E.Y., Bareyan, D., and Daynes, R.A. (2011). J. Immunol. 186, 697–707. Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011). Nature 479, 547–551. Luo, X., Fu, Y., Loza, A.J., Murali, B., Leahy, K.M., Ruhland, M.K., Gang, M., Su, X., Zamani, A., Shi, Y., et al. (2016). Cell Rep. 14, 82–92. Mun˜oz-Espı´n, D., and Serrano, M. (2014). Nat. Rev. Mol. Cell Biol. 15, 482–496. Ruhland, M.K., Loza, A.J., Capietto, A.-H., Luo, X., Knolhoff, B.L., Flanagan, K.C., Belt, B.A., Alspach, E., Leahy, K., Luo, J., et al. (2016). Nat. Commun. 7, 11762. Talmadge, J.E., and Gabrilovich, D.I. (2013). Nat. Rev. Cancer 13, 739–752. Toso, A., Revandkar, A., Di Mitri, D., Guccini, I., Proietti, M., Sarti, M., Pinton, S., Zhang, J., Kalathur, M., Civenni, G., et al. (2014). Cell Rep. 9, 75–89. Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., and Lowe, S.W. (2007). Nature 445, 656–660.
Previews and should facilitate a more in-depth analysis of SOX2 function in the context of 3q26-driven LSCC.
Hammerman, P.S., Lawrence, M.S., Voet, D., Jing, R., Cibulskis, K., Sivachenko, A., Stojanov, P., McKenna, A., Lander, E.S., Gabriel, S., et al.; Cancer Genome Atlas Research Network (2012). Nature 489, 519–525.
REFERENCES
Hayes, S.A., Hudson, A.L., Clarke, S.J., Molloy, M.P., and Howell, V.M. (2014). Semin. Cell Dev. Biol. 27, 118–127.
Ferone, G., Song, Y.J., Sutherland, K.D., Bhaskaran, R., Monkhorst, K., Lambooij, J.P., Proost, N., Gargiulo, G., and Berns, A. (2016). Cancer Cell 30, this issue, 519–532. Fields, A.P., Justilien, V., and Murray, N.R. (2016). Adv. Biol. Regul. 60, 47–63.
Justilien, V., and Fields, A.P. (2009). Oncogene 28, 3597–3607. Justilien, V., Walsh, M.P., Ali, S.A., Thompson, E.A., Murray, N.R., and Fields, A.P. (2014). Cancer Cell 25, 139–151.
Mukhopadhyay, A., Berrett, K.C., Kc, U., Clair, P.M., Pop, S.M., Carr, S.R., Witt, B.L., and Oliver, T.G. (2014). Cell Rep. 8, 40–49. Siegel, R.L., Miller, K.D., and Jemal, A. (2016). CA Cancer J. Clin. 66, 7–30. Wang, Y., Zhang, Z., Yan, Y., Lemon, W.J., LaRegina, M., Morrison, C., Lubet, R., and You, M. (2004). Cancer Res. 64, 1647–1654. Xu, C., Fillmore, C.M., Koyama, S., Wu, H., Zhao, Y., Chen, Z., Herter-Sprie, G.S., Akbay, E.A., Tchaicha, J.H., Altabef, A., et al. (2014). Cancer Cell 25, 590–604.
Senescence and Cancer: In the Name of Immunosuppression Susana Llanos1,* and Manuel Serrano1,* 1Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain *Correspondence: [email protected] (S.L.), [email protected] (M.S.) http://dx.doi.org/10.1016/j.ccell.2016.09.015
Senescent cells and cancer cells recruit immunosuppressive myeloid cells. In this issue of Cancer Cell, Eggert et al. report that senescent cells recruit immature myeloid cells (iMCs) through the secretion of the CCL2 cytokine and that these iMCs have pro- or anti-tumorigenic activities, depending on the cellular context.
Cellular senescence is a stress response that restricts the proliferation of damaged cells and thus plays an important role in tumor suppression. A significant feature of senescent cells is the secretion of many proteins, including immune-attracting cytokines and chemokines, growth factors, and matrix remodeling proteases, collectively known as the senescenceassociated secretory phenotype (SASP). A prominent consequence of the SASP is the recruitment of immune cells; however, these immune cells have paradoxically antagonistic effects on cancer. On one hand, T cells, macrophages, and natural killer cells mediate the removal of senescent cells. This process, known as senescence surveillance or clearance, contributes to prevent tumor initiation (Kang et al., 2011) and also participates in the regression of cancers that have undergone p53-mediated senescence (Xue et al., 2007). On the other hand, senescent cells recruit immunosuppressive myeloid cells that create an immunotolerant context that allows tumor growth (Luo
et al., 2016; Ruhland et al., 2016; Toso et al., 2014). Immunosuppressive myeloid cells are generally defined by the surface markers CD11b and Gr1 (CD11b+Gr1+). In the absence of tumor-derived factors, CD11b+Gr1+ cells retain the ability to differentiate into dendritic cells, macrophages, or neutrophils, and thereby are referred to as immature myeloid cells (iMCs). However, in the presence of tumor-derived factors, CD11b+Gr1+ cells lose their capacity to differentiate and inhibit the function of other immune cells, namely T cells, dendritic cells, macrophages, and natural killer (NK) cells, thereby creating an immunotolerant environment that allows tumor progression. These tumor-associated CD11b+Gr1+ cells are generally known as myeloidderived suppressive cells (MDSCs) (Talmadge and Gabrilovich, 2013). It remains to be defined to what extent CD11b+Gr1+ cells in a non-tumoral context (i.e., iMCs) are different from CD11b+Gr1+ cells in a tumoral context (i.e., MDSCs).
In the current issue of Cancer Cell, Eggert et al. report that senescence-recruited CD11b+Gr1+ cells can be anti- or pro-tumorigenic, depending on the cellular context (Eggert et al., 2016). The current study is based on a mouse model of oncogene-induced senescence (OIS) by intrahepatic delivery of oncogenic NrasG12V. In this biological setting, clearance of senescent hepatocytes prevents neoplastic progression (Kang et al., 2011). Eggert and colleges demonstrate that the production of the cytokine CCL2 (also known as MCP-1) by senescent cells plays a key role in the recruitment of immature CD11b+Gr1+ cells that subsequently mature into macrophages. The authors observe that these macrophages are relevant (1) for the establishment and reinforcement of senescence through the production of immune-secreted factors in a feed-forward loop and (2) for the clearing of senescent cells (Figure 1). Accordingly, mice deficient for the CCL2 receptor CCR2 are highly susceptible to the development of hepatocellular
Cancer Cell 30, October 10, 2016 ª 2016 Elsevier Inc. 507
Cancer Cell
Previews ANTI-TUMORAL
CD11b+Gr1+ myeloid cells
PRO-TUMORAL
maturation
CCL2
Tumor cells
Senescent cells
Macrophages Figure 1. Crosstalk between Senescent Cells and Cancer Cells Dictates the Anti- or Protumorigenic Activity of Immature Myeloid Cells In the absence of tumor cells, senescence-recruited CD11b+Gr1+ myeloid cells differentiate into macrophages that mediate senescence clearance and tumor protection. In the presence of tumor-secreted factors, CD11b+Gr1+ cells fail to differentiate and their immunosuppressive activities allow neoplastic cells to evade the immune system and promote tumor growth.
carcinomas (HCCs) upon introduction of NrasG12V. Interestingly, however, cancer cells can subvert to their advantage the activity of the myeloid cells recruited by senescent cells. Eggert and colleagues observe that when hepatocellular tumor cells infiltrate livers containing senescent cells, myeloid cells accumulate and create a potent immunotolerant environment rather than maturing into macrophages. This concept is in agreement with previous publications reporting that senescent cells promote cancer growth through the recruitment of immunosuppressive CD11b+Gr1+ cells (Luo et al., 2016; Ruhland et al., 2016; Toso et al., 2014). Based on their findings in a non-tumoral context, Eggert and colleagues demonstrate that senescent cells also recruit CD11b+Gr1+ cells through the CCL2-CCR2 axis in the presence of tumor cells. In this case, however, HCC cells hinder the differentiation of immature CD11b+Gr1+ cells into macrophages (Figure 1). Importantly, these tumor-educated CD11b+Gr1+ cells are now blocked in an immunosuppressive state that favors tumor growth. Also, the absence of macrophage differentiation allows the accumulation of senescent cells, which further amplifies the recruitment of CD11b+Gr1+ cells via CCL2. Supporting these observations, Eggert 508 Cancer Cell 30, October 10, 2016
et al. report that in HCC patients, peritumoral senescence is associated with increased CCL2 expression, infiltration of immunosuppressive cells, reduced NK cells, and poorer prognosis. These observations have therapeutic implications. The most immediate one is that pharmacologically interfering with the SASP or its targets (for example, using CCR2 antagonists) may benefit HCC patients by reducing the recruitment of immunosuppressive cells. However, as pointed out by the authors, this type of intervention may promote tumor growth in patients at risk of developing liver cancer, such as those with chronic liver damage. The work by Eggert and colleges also suggests that in situations in which senescence and tumor cells coexist, as in the case of chemotherapy-treated tumors, interfering with the secretome of tumor cells may reactivate the differentiation of CD11b+Gr1+ cells into macrophages, thereby disrupting immunotolerance and triggering the elimination of both tumor cells and chemotherapyinduced senescent cells. In this regard, it would be important to identify the key tumor-secreted factors that prevent the differentiation of CD11b+Gr1+ cells into macrophages. In addition, this work poses new questions about how tumor cells crosstalk to senescent cells. It is
conceivable that, besides interacting with immune cells, the tumor secretome may directly modulate the function of senescent cells or the senescent secretory phenotype. Finally, one interesting implication of this study is that, in the absence of a cancer environment, senescence-recruited CD11b+Gr1+ cells may have beneficial implications beyond protection from cancer initiation. In particular, senescent cells accumulate in many human pathologies and during aging, and are responsible, at least in part, for the loss of tissue function (Mun˜oz-Espı´n and Serrano, 2014). Interestingly, it has been reported that CD11b+Gr1+ cells increase in the blood and lymphoid organs during aging (Enioutina et al., 2011). These elevated levels of CD11b+Gr1+ cells can now be explained as a consequence of the accumulation of senescent cells during aging. Conceivably, CD11b+Gr1+ cells may elicit the disposal of agingassociated senescent cells thereby reducing tissue dysfunction during aging. In relation to this, potentiating the activity of CD11b+Gr1+ cells may have beneficial and therapeutic effects on aging and on multiple senescence-associated diseases. REFERENCES Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Median-Echeverz, J., Longerich, T., Forges, M., Reinsinger, F., et al. (2016). Cancer Cell 30, this issue, 533–547. Enioutina, E.Y., Bareyan, D., and Daynes, R.A. (2011). J. Immunol. 186, 697–707. Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011). Nature 479, 547–551. Luo, X., Fu, Y., Loza, A.J., Murali, B., Leahy, K.M., Ruhland, M.K., Gang, M., Su, X., Zamani, A., Shi, Y., et al. (2016). Cell Rep. 14, 82–92. Mun˜oz-Espı´n, D., and Serrano, M. (2014). Nat. Rev. Mol. Cell Biol. 15, 482–496. Ruhland, M.K., Loza, A.J., Capietto, A.-H., Luo, X., Knolhoff, B.L., Flanagan, K.C., Belt, B.A., Alspach, E., Leahy, K., Luo, J., et al. (2016). Nat. Commun. 7, 11762. Talmadge, J.E., and Gabrilovich, D.I. (2013). Nat. Rev. Cancer 13, 739–752. Toso, A., Revandkar, A., Di Mitri, D., Guccini, I., Proietti, M., Sarti, M., Pinton, S., Zhang, J., Kalathur, M., Civenni, G., et al. (2014). Cell Rep. 9, 75–89. Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., and Lowe, S.W. (2007). Nature 445, 656–660.