Leukemia & Lymphoma, August 2014; 55(8): 1699–1700 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.881481
COMMENTARY
Lenalidomide and T-cell homeostasis: tolerating immune reconstitution after autologous stem cell transplant Chava Perry1 & Aaron Polliack2 1Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel and 2Department of Hematology, Hadassah University Hospital, Jerusalem, Israel
The immune system is activated in patients who develop malignancy, the adaptive immune response playing a major role in this battle to eliminate neoplastic cells displaying tumor-specific antigens (Ags). CD4 ⫹ T cells coordinate these adaptive immune responses both through secretion of cytokines and via direct intercellular contacts, while CD8 ⫹ T lymphocytes are pre-committed as cytotoxic effector cells. After stimulation with cognate Ag, T cells expand and differentiate into either effector T cells (Teff ), which mostly die after clearing the pathogen, or long-lived memory T cells, mediating long-term immunity [1]. Other than Ag specificity, T cell subsets have a number of diverse features relating to gene expression profiles, cellular metabolism, cytokine secretion, localization and proliferative potential. The latter functions all influence basic T cell anti-tumor activity [2,3]. T cell subsets can be classified according to expression of surface markers, which are readily detectable by fluorescence activated cell scanner (FACS). Co-expression of the lymphoid homing molecules l-selectin and CC-chemokine receptor 7 (CCR7) allows T cells to repopulate secondary lymphoid structures, where they check professional Ag presenting cells for the presence of cognate Ag. T cell subsets displaying both l-selectin and CCR7 include naive T cells, precursors of most Ag experienced T cells, as well as two subsets of Ag experienced memory T cells – the T memory stem cell (TSCM) and central memory T cells (TCM), which both have high proliferative potential [4]. The more differentiated Ag experienced T cells, the effector memory (TEM) and terminally effector (TEFF) cells, lose expression of l-selectin and CCR7, which allows them to reside in the periphery rather than home to lymphoid tissues [5]. Once activated, these cells release large amounts of inflammatory cytokines and rapidly destroy Ag expressing targets, but appear to have limited proliferative potential. TEFF cells re-express CD45RA, the longest isoform of CD45, present on naive T cells, which is subsequently lost upon T cell activation. TEFF are highly differentiated cells, and
their proportion increases with aging [6]. Recent studies investigating T cell subtype properties during adaptive cell transfer revealed that the less differentiated (TSCM and TCM) cells have increased proliferative and survival capacities, and are thus better equipped to mediate anti-tumor responses, compared to more differentiated TEM and TEFF [5]. While the ability of T cells to suppress the rejection of implanted tumors was already reported in the 1970s, it was only during the past two decades that regulatory T cells (Tregs) were shown to be present in tumors, inducing immune tolerance to cancer cells, and that an increased Treg/Teff ratio is associated with poor prognosis in these patients [7,8]. When the kinetics of the anti-tumor immune response was investigated, it was soon realized that the Tregs response is a very early tumor-specific response. Apparently, tumor-derived Ags able to stimulate Tregs are self-Ags, and self-specific activated memory Tregs, constantly activated by self-Ags and which are highly potent immune-suppressant cells, are in fact the first to react, even before the induction of tumor-associated Ag-specific Teff cells [9]. It appears that memory Teff cells are more resistant to Tregs-mediated suppression, are strongly tumoricidal, and their presence within the tumor tissue is associated with a favorable prognosis [10]. However, the kinetics of Teff expansion is slower than that of activated memory Tregs, resulting in a delayed anti-tumor response, which enables the establishment of an immune-subversive environment. Thus, the dynamic timing and kinetics of Tregs and Teff cells are dependent on their memory status, and this determines the eventual fate of the tumor. In this issue of Leukemia and Lymphoma, Clave et al. investigated the effects of lenalidomide (LEN) on T cell immune reconstitution in patients with multiple myeloma (MM) after autologous stem cell transplant (ASCT) [11]. They compared T cell reconstitution in patients who received LEN consolidation and maintenance to that in others not receiving treatment following ASCT. In transplanted patients receiving
Correspondence: Chava Perry, MD, PhD, Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, 6 Weizman St., Tel Aviv, 64239, Israel. Tel: 972-3-6973576. Fax: 972-3-6974452. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
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LEN they noted delayed reconstitution of thymic T cells and CD4 ⫹ and CD8 ⫹ TEFF cells, but not of TEM and TCM subsets. Furthermore, in vitro treatment of healthy donor naive T cells with LEN resulted in an increase in TCM and TEM and a decrease in TEFF subpopulations, suggesting that LEN not only activates T cells but also blocks differentiation into TEFF. Moreover, a sustained increase in Treg cells was detected in the LEN treated group. While LEN has significant clinical activity in MM as well as in chronic lymphocytic leukemia and some lymphomas, affecting both tumor cells and the surrounding microenvironment, its precise mechanism of action is still unclear. This long-lasting, LEN-induced immune modulation reported here [11] is indeed intriguing, posing a number of possible questions. How does LEN block differentiation of naive T cells into TEFF? Does the delay in reconstitution of the TEFF cells together with an increase in Tregs proportion predispose or aid in the promotion of an immune-subversive environment? It seems that metabolic changes such as augmented glycolytic flux drive T cells toward a terminally differentiated state, while inhibition of this phenomenon preserves and enhances the generation of earlier memory T cells [12]. It is indeed possible that LEN affects glycolytic metabolism in T cells, thereby supervising and directing “traffic” at cell differentiation crossroads. Another explanation may relate to the previously reported LEN-induced activation of the Wnt signaling pathway, shown to be associated with arrested Teff differentiation [13,14]. In this respect, no adverse antimyeloma effect was observed in patients in the LEN-maintenance group, as these patients had a better progression-free survival (PFS) than the control group, which is in agreement with previous results reported in a larger patient cohort [15]. In addition, there was no increase in infectious complications in these patients. So, in conclusion, one may ask: do these observations have possible clinical implications? Could they perhaps explain the finding that second malignancies appear to be associated with prolonged maintenance treatment with LEN in patients with MM after ASCT? It is possible that the relatively fast recovery of the less-differentiated memory T cells (TCM, TEM) enables the induction and preservation of the anti-myeloma response, while the increase in Treg levels may also contribute to antimyeloma effects. Unlike lymphoma and other solid tumors, MM is associated with reduced levels of Tregs. However,
regarding immune surveillance against newly arising tumors in general, the long-standing increase in Treg levels and the adverse Treg/Teff ratio may induce tolerance for tumor neoantigens, thereby resulting in an enhanced predisposition to second malignancies.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Geginat J, Paroni M, Facciotti F, et al. The CD4-centered universe of human T cell subsets. Semin Immunol 2013;25:252–262. [2] Klebanoff CA , Gattinoni L, Restifo NP. CD8 ⫹ T-cell memory in tumor immunology and immunotherapy. Immunol Rev 2006; 211:214–224. [3] Weng NP, Araki Y, Subedi K. The molecular basis of the memory T cell response. Nat Rev Immunol 2012;4:306–315. [4] Sallusto F, Lenig D, Forester, et al. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–712. [5] Klebanoff CA , Gattinoni L, Restifo NP. Sorting through subsets: which T cell population mediate highly effective adoptive immunotherapy? J Immunother 2012;35:651–660. [6] Henson SM, Riddell NE, Akbar AN. Properties of end-stage human T cells defined by CD45RA re-expression. Curr Opin Immunol 2012;24:476–481. [7] Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest 2007;117:1167–1174. [8] Beyer M, Schultze JL. Regulatory T cells in cancer. Blood 2006;108:804–811. [9] Darrasse-Jeze G, Bergot AS, Durgeau A , et al. Tumor emergence is sensed by self-specific CD44hi memory Tregs that create dominant tolerogenic environment for tumors in mice. J Clin Invest 2009;119: 2648–2662. [10] Pages F, Berger A , Camus M, et al. Effector memory T cells, early metastasis and survival in colorectal cancer. N Engl J Med 2005;353:2654–2666. [11] Clave E, Douay C, Coman T, et al. Lenalidomide consolidation and maintenance therapy after autologous stem cell transplant for multiple myeloma induces persistent changes in T-cell homeostasis. Leuk Lymphoma 2014;55:1788–1795. [12] Sukumar M, Liu J, Ji Y, et al. Inhibiting glycolytic metabolism enhances CD8 ⫹ T cell memory and anti tumor function. J Clin Invest 2013;123:4479–4488. [13] Muralidharan S, Hanley PJ, Liu E, et al. Activation of Wnt signaling arrests effector differentiation in human peripheral and cord bloodderived T lymphocytes. J Immunol 2011;187:5221–5232. [14] Bjorklund CC, Ma W, Wang ZQ, et al. Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. J Biol Chem 2011;286:11009–11020. [15] Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–1791.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
COMMENTARY
Lenalidomide and T-cell homeostasis: tolerating immune reconstitution after autologous stem cell transplant Chava Perry1 & Aaron Polliack2 1Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel and 2Department of Hematology, Hadassah University Hospital, Jerusalem, Israel
The immune system is activated in patients who develop malignancy, the adaptive immune response playing a major role in this battle to eliminate neoplastic cells displaying tumor-specific antigens (Ags). CD4 ⫹ T cells coordinate these adaptive immune responses both through secretion of cytokines and via direct intercellular contacts, while CD8 ⫹ T lymphocytes are pre-committed as cytotoxic effector cells. After stimulation with cognate Ag, T cells expand and differentiate into either effector T cells (Teff ), which mostly die after clearing the pathogen, or long-lived memory T cells, mediating long-term immunity [1]. Other than Ag specificity, T cell subsets have a number of diverse features relating to gene expression profiles, cellular metabolism, cytokine secretion, localization and proliferative potential. The latter functions all influence basic T cell anti-tumor activity [2,3]. T cell subsets can be classified according to expression of surface markers, which are readily detectable by fluorescence activated cell scanner (FACS). Co-expression of the lymphoid homing molecules l-selectin and CC-chemokine receptor 7 (CCR7) allows T cells to repopulate secondary lymphoid structures, where they check professional Ag presenting cells for the presence of cognate Ag. T cell subsets displaying both l-selectin and CCR7 include naive T cells, precursors of most Ag experienced T cells, as well as two subsets of Ag experienced memory T cells – the T memory stem cell (TSCM) and central memory T cells (TCM), which both have high proliferative potential [4]. The more differentiated Ag experienced T cells, the effector memory (TEM) and terminally effector (TEFF) cells, lose expression of l-selectin and CCR7, which allows them to reside in the periphery rather than home to lymphoid tissues [5]. Once activated, these cells release large amounts of inflammatory cytokines and rapidly destroy Ag expressing targets, but appear to have limited proliferative potential. TEFF cells re-express CD45RA, the longest isoform of CD45, present on naive T cells, which is subsequently lost upon T cell activation. TEFF are highly differentiated cells, and
their proportion increases with aging [6]. Recent studies investigating T cell subtype properties during adaptive cell transfer revealed that the less differentiated (TSCM and TCM) cells have increased proliferative and survival capacities, and are thus better equipped to mediate anti-tumor responses, compared to more differentiated TEM and TEFF [5]. While the ability of T cells to suppress the rejection of implanted tumors was already reported in the 1970s, it was only during the past two decades that regulatory T cells (Tregs) were shown to be present in tumors, inducing immune tolerance to cancer cells, and that an increased Treg/Teff ratio is associated with poor prognosis in these patients [7,8]. When the kinetics of the anti-tumor immune response was investigated, it was soon realized that the Tregs response is a very early tumor-specific response. Apparently, tumor-derived Ags able to stimulate Tregs are self-Ags, and self-specific activated memory Tregs, constantly activated by self-Ags and which are highly potent immune-suppressant cells, are in fact the first to react, even before the induction of tumor-associated Ag-specific Teff cells [9]. It appears that memory Teff cells are more resistant to Tregs-mediated suppression, are strongly tumoricidal, and their presence within the tumor tissue is associated with a favorable prognosis [10]. However, the kinetics of Teff expansion is slower than that of activated memory Tregs, resulting in a delayed anti-tumor response, which enables the establishment of an immune-subversive environment. Thus, the dynamic timing and kinetics of Tregs and Teff cells are dependent on their memory status, and this determines the eventual fate of the tumor. In this issue of Leukemia and Lymphoma, Clave et al. investigated the effects of lenalidomide (LEN) on T cell immune reconstitution in patients with multiple myeloma (MM) after autologous stem cell transplant (ASCT) [11]. They compared T cell reconstitution in patients who received LEN consolidation and maintenance to that in others not receiving treatment following ASCT. In transplanted patients receiving
Correspondence: Chava Perry, MD, PhD, Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, 6 Weizman St., Tel Aviv, 64239, Israel. Tel: 972-3-6973576. Fax: 972-3-6974452. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1699
1700
C. Perry & A. Polliack
LEN they noted delayed reconstitution of thymic T cells and CD4 ⫹ and CD8 ⫹ TEFF cells, but not of TEM and TCM subsets. Furthermore, in vitro treatment of healthy donor naive T cells with LEN resulted in an increase in TCM and TEM and a decrease in TEFF subpopulations, suggesting that LEN not only activates T cells but also blocks differentiation into TEFF. Moreover, a sustained increase in Treg cells was detected in the LEN treated group. While LEN has significant clinical activity in MM as well as in chronic lymphocytic leukemia and some lymphomas, affecting both tumor cells and the surrounding microenvironment, its precise mechanism of action is still unclear. This long-lasting, LEN-induced immune modulation reported here [11] is indeed intriguing, posing a number of possible questions. How does LEN block differentiation of naive T cells into TEFF? Does the delay in reconstitution of the TEFF cells together with an increase in Tregs proportion predispose or aid in the promotion of an immune-subversive environment? It seems that metabolic changes such as augmented glycolytic flux drive T cells toward a terminally differentiated state, while inhibition of this phenomenon preserves and enhances the generation of earlier memory T cells [12]. It is indeed possible that LEN affects glycolytic metabolism in T cells, thereby supervising and directing “traffic” at cell differentiation crossroads. Another explanation may relate to the previously reported LEN-induced activation of the Wnt signaling pathway, shown to be associated with arrested Teff differentiation [13,14]. In this respect, no adverse antimyeloma effect was observed in patients in the LEN-maintenance group, as these patients had a better progression-free survival (PFS) than the control group, which is in agreement with previous results reported in a larger patient cohort [15]. In addition, there was no increase in infectious complications in these patients. So, in conclusion, one may ask: do these observations have possible clinical implications? Could they perhaps explain the finding that second malignancies appear to be associated with prolonged maintenance treatment with LEN in patients with MM after ASCT? It is possible that the relatively fast recovery of the less-differentiated memory T cells (TCM, TEM) enables the induction and preservation of the anti-myeloma response, while the increase in Treg levels may also contribute to antimyeloma effects. Unlike lymphoma and other solid tumors, MM is associated with reduced levels of Tregs. However,
regarding immune surveillance against newly arising tumors in general, the long-standing increase in Treg levels and the adverse Treg/Teff ratio may induce tolerance for tumor neoantigens, thereby resulting in an enhanced predisposition to second malignancies.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Geginat J, Paroni M, Facciotti F, et al. The CD4-centered universe of human T cell subsets. Semin Immunol 2013;25:252–262. [2] Klebanoff CA , Gattinoni L, Restifo NP. CD8 ⫹ T-cell memory in tumor immunology and immunotherapy. Immunol Rev 2006; 211:214–224. [3] Weng NP, Araki Y, Subedi K. The molecular basis of the memory T cell response. Nat Rev Immunol 2012;4:306–315. [4] Sallusto F, Lenig D, Forester, et al. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–712. [5] Klebanoff CA , Gattinoni L, Restifo NP. Sorting through subsets: which T cell population mediate highly effective adoptive immunotherapy? J Immunother 2012;35:651–660. [6] Henson SM, Riddell NE, Akbar AN. Properties of end-stage human T cells defined by CD45RA re-expression. Curr Opin Immunol 2012;24:476–481. [7] Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest 2007;117:1167–1174. [8] Beyer M, Schultze JL. Regulatory T cells in cancer. Blood 2006;108:804–811. [9] Darrasse-Jeze G, Bergot AS, Durgeau A , et al. Tumor emergence is sensed by self-specific CD44hi memory Tregs that create dominant tolerogenic environment for tumors in mice. J Clin Invest 2009;119: 2648–2662. [10] Pages F, Berger A , Camus M, et al. Effector memory T cells, early metastasis and survival in colorectal cancer. N Engl J Med 2005;353:2654–2666. [11] Clave E, Douay C, Coman T, et al. Lenalidomide consolidation and maintenance therapy after autologous stem cell transplant for multiple myeloma induces persistent changes in T-cell homeostasis. Leuk Lymphoma 2014;55:1788–1795. [12] Sukumar M, Liu J, Ji Y, et al. Inhibiting glycolytic metabolism enhances CD8 ⫹ T cell memory and anti tumor function. J Clin Invest 2013;123:4479–4488. [13] Muralidharan S, Hanley PJ, Liu E, et al. Activation of Wnt signaling arrests effector differentiation in human peripheral and cord bloodderived T lymphocytes. J Immunol 2011;187:5221–5232. [14] Bjorklund CC, Ma W, Wang ZQ, et al. Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. J Biol Chem 2011;286:11009–11020. [15] Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–1791.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
