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Abscopal Effect
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Mohammad K. Khan – One of the best experts on this subject based on the ideXlab platform.
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Tumor-draining lymph node is important for a robust Abscopal Effect stimulated by radiotherapy.
Journal for immunotherapy of cancer, 2020Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, Judong Lee, Christiane Sigrid Eberhardt, Andres Wieland, David H. Lawson, Walter J. Curran, Rafi Ahmed, Mohammad K. KhanAbstract:Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (Abscopal Effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated Abscopal response. Methods We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells. Results We show that local tumor irradiation improves distant tumor control (Abscopal Effect). Depletion of CD8+ T-cells significantly reduced this Abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8+ T-cell subset which then differentiate into terminally differentiated Effectors. These terminally differentiated Effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8+ T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The Effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8+ and stem-like CD8+ T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the Abscopal Effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8+ T-cells and stem-like CD8+ T-cells in both the irradiated and unirradiated tumor. Conclusions These correlative results suggest the tumor-draining LN may be an important mediator of the Abscopal Effect by serving as a stem-like CD8+ T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.
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Abstract 526: Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the Abscopal Effect
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, Christiane Sigrid Eberhardt, David H. Lawson, Walter J. Curran, Rafi Ahmed, Andreas Wieland, Mohammad K. KhanAbstract:Purpose: PD-1 and PD-L1 antagonists are efficacious because cancer induces T-cell exhaustion via upregulation of PD-L1 and persistent antigen exposure. Our lab, has shown that the proliferative burst following αPD-L1 therapy of exhausted CD8+PD-1+T-cells is restricted to a “stem-like” CD8+T-cell subset in a murine chronic viral infection model. The role of these stem-like CD8+T-cells in malignancies and whether these cells respond to other immuno-stimulation including radiotherapy (RT) is unknown. RT’s immuno-stimulation includes acting as an in-situ vaccine by liberating cryptic tumor neo-antigens, generating a potent anti-tumor CD8+T-cell response, synergizing with αPD-1/L1 and leading to control at distant sites of disease outside the radiation field (Abscopal Effect). In initial studies, we found these stem-like CD8+T-cells in B16F10 tumors and at high frequencies in the tumor-draining lymph nodes (TDLN) of immunocompetent mice. Here, we investigated: (1) the impact of tumor-directed RT on this stem-like CD8+T-cell population in the tumor and TDLN in the context of an Abscopal response, and (2) due to the high frequency of stem-like CD8+T-cells in the TDLN, whether depletion of lymphocytes from the TDLN via RT influenced the Abscopal Effect. Experimental Design: We developed a preclinical model of oligo-metastatic melanoma to evaluate the role of stem-like CD8+ T-cells and the TDLN in the Abscopal Effect. This was done with unilateral tumor-directed RT with or without TDLN-directed RT. This was also done in the presence and absence of αPD-L1. Results: Tumor-directed RT improved local tumor control and induced an Abscopal response with a concomitant increase in tumor infiltrating tumor-specific stem-like CD8+T-cells. Tumor-specific stem-like CD8+T-cells were also observed in the TDLN of tumors on both sides. Importantly, the tumor-directed RT increased tumor-specific T-cell proliferation in the TDLNs bilaterally despite only being targeted at one tumor. Given this robust proliferative response and the high frequency of stem-like CD8+T-cells in the TDLN, we next evaluated the role of the TDLN in mediating the Abscopal Effect. We found that the Abscopal Effect is impaired if the TDLN is lymphocyte depleted with TDLN-directed RT in the presence or absence of αPD-L1. Additionally, the tumor-directed RT mediated increase in stem-like T-cells in the irradiated and unirradiated tumor was abrogated with TDLN-directed RT. Conclusion: Our results demonstrate slowed distant tumor growth following irradiation of a local site and that this correlates with an increase in tumor-infiltrating stem-like CD8+T-cells which is reduced with TDLN-directed RT. These data suggest a critical role for both the stem-like CD8+T-cells and the TDLN in mediating the Abscopal Effect. Citation Format: Zachary S. Buchwald, Tahseen H. Nasti, Christiane S. Eberhardt, Andreas Wieland, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K. Khan. Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the Abscopal Effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 526.
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abstract 526 tumor draining lymph node irradiation reduces tumor infiltrating stem like cd8 t cells and abrogates the Abscopal Effect
Cancer Research, 2019Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, David H. Lawson, Walter J. Curran, Rafi Ahmed, Andreas Wieland, Christiane S Eberhardt, Mohammad K. KhanAbstract:Purpose: PD-1 and PD-L1 antagonists are efficacious because cancer induces T-cell exhaustion via upregulation of PD-L1 and persistent antigen exposure. Our lab, has shown that the proliferative burst following αPD-L1 therapy of exhausted CD8+PD-1+T-cells is restricted to a “stem-like” CD8+T-cell subset in a murine chronic viral infection model. The role of these stem-like CD8+T-cells in malignancies and whether these cells respond to other immuno-stimulation including radiotherapy (RT) is unknown. RT’s immuno-stimulation includes acting as an in-situ vaccine by liberating cryptic tumor neo-antigens, generating a potent anti-tumor CD8+T-cell response, synergizing with αPD-1/L1 and leading to control at distant sites of disease outside the radiation field (Abscopal Effect). In initial studies, we found these stem-like CD8+T-cells in B16F10 tumors and at high frequencies in the tumor-draining lymph nodes (TDLN) of immunocompetent mice. Here, we investigated: (1) the impact of tumor-directed RT on this stem-like CD8+T-cell population in the tumor and TDLN in the context of an Abscopal response, and (2) due to the high frequency of stem-like CD8+T-cells in the TDLN, whether depletion of lymphocytes from the TDLN via RT influenced the Abscopal Effect. Experimental Design: We developed a preclinical model of oligo-metastatic melanoma to evaluate the role of stem-like CD8+ T-cells and the TDLN in the Abscopal Effect. This was done with unilateral tumor-directed RT with or without TDLN-directed RT. This was also done in the presence and absence of αPD-L1. Results: Tumor-directed RT improved local tumor control and induced an Abscopal response with a concomitant increase in tumor infiltrating tumor-specific stem-like CD8+T-cells. Tumor-specific stem-like CD8+T-cells were also observed in the TDLN of tumors on both sides. Importantly, the tumor-directed RT increased tumor-specific T-cell proliferation in the TDLNs bilaterally despite only being targeted at one tumor. Given this robust proliferative response and the high frequency of stem-like CD8+T-cells in the TDLN, we next evaluated the role of the TDLN in mediating the Abscopal Effect. We found that the Abscopal Effect is impaired if the TDLN is lymphocyte depleted with TDLN-directed RT in the presence or absence of αPD-L1. Additionally, the tumor-directed RT mediated increase in stem-like T-cells in the irradiated and unirradiated tumor was abrogated with TDLN-directed RT. Conclusion: Our results demonstrate slowed distant tumor growth following irradiation of a local site and that this correlates with an increase in tumor-infiltrating stem-like CD8+T-cells which is reduced with TDLN-directed RT. These data suggest a critical role for both the stem-like CD8+T-cells and the TDLN in mediating the Abscopal Effect. Citation Format: Zachary S. Buchwald, Tahseen H. Nasti, Christiane S. Eberhardt, Andreas Wieland, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K. Khan. Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the Abscopal Effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 526.
Zachary S. Buchwald – One of the best experts on this subject based on the ideXlab platform.
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Tumor-draining lymph node is important for a robust Abscopal Effect stimulated by radiotherapy.
Journal for immunotherapy of cancer, 2020Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, Judong Lee, Christiane Sigrid Eberhardt, Andres Wieland, David H. Lawson, Walter J. Curran, Rafi Ahmed, Mohammad K. KhanAbstract:Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (Abscopal Effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated Abscopal response. Methods We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells. Results We show that local tumor irradiation improves distant tumor control (Abscopal Effect). Depletion of CD8+ T-cells significantly reduced this Abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8+ T-cell subset which then differentiate into terminally differentiated Effectors. These terminally differentiated Effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8+ T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The Effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8+ and stem-like CD8+ T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the Abscopal Effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8+ T-cells and stem-like CD8+ T-cells in both the irradiated and unirradiated tumor. Conclusions These correlative results suggest the tumor-draining LN may be an important mediator of the Abscopal Effect by serving as a stem-like CD8+ T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.
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Abstract 526: Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the Abscopal Effect
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, Christiane Sigrid Eberhardt, David H. Lawson, Walter J. Curran, Rafi Ahmed, Andreas Wieland, Mohammad K. KhanAbstract:Purpose: PD-1 and PD-L1 antagonists are efficacious because cancer induces T-cell exhaustion via upregulation of PD-L1 and persistent antigen exposure. Our lab, has shown that the proliferative burst following αPD-L1 therapy of exhausted CD8+PD-1+T-cells is restricted to a “stem-like” CD8+T-cell subset in a murine chronic viral infection model. The role of these stem-like CD8+T-cells in malignancies and whether these cells respond to other immuno-stimulation including radiotherapy (RT) is unknown. RT’s immuno-stimulation includes acting as an in-situ vaccine by liberating cryptic tumor neo-antigens, generating a potent anti-tumor CD8+T-cell response, synergizing with αPD-1/L1 and leading to control at distant sites of disease outside the radiation field (Abscopal Effect). In initial studies, we found these stem-like CD8+T-cells in B16F10 tumors and at high frequencies in the tumor-draining lymph nodes (TDLN) of immunocompetent mice. Here, we investigated: (1) the impact of tumor-directed RT on this stem-like CD8+T-cell population in the tumor and TDLN in the context of an Abscopal response, and (2) due to the high frequency of stem-like CD8+T-cells in the TDLN, whether depletion of lymphocytes from the TDLN via RT influenced the Abscopal Effect. Experimental Design: We developed a preclinical model of oligo-metastatic melanoma to evaluate the role of stem-like CD8+ T-cells and the TDLN in the Abscopal Effect. This was done with unilateral tumor-directed RT with or without TDLN-directed RT. This was also done in the presence and absence of αPD-L1. Results: Tumor-directed RT improved local tumor control and induced an Abscopal response with a concomitant increase in tumor infiltrating tumor-specific stem-like CD8+T-cells. Tumor-specific stem-like CD8+T-cells were also observed in the TDLN of tumors on both sides. Importantly, the tumor-directed RT increased tumor-specific T-cell proliferation in the TDLNs bilaterally despite only being targeted at one tumor. Given this robust proliferative response and the high frequency of stem-like CD8+T-cells in the TDLN, we next evaluated the role of the TDLN in mediating the Abscopal Effect. We found that the Abscopal Effect is impaired if the TDLN is lymphocyte depleted with TDLN-directed RT in the presence or absence of αPD-L1. Additionally, the tumor-directed RT mediated increase in stem-like T-cells in the irradiated and unirradiated tumor was abrogated with TDLN-directed RT. Conclusion: Our results demonstrate slowed distant tumor growth following irradiation of a local site and that this correlates with an increase in tumor-infiltrating stem-like CD8+T-cells which is reduced with TDLN-directed RT. These data suggest a critical role for both the stem-like CD8+T-cells and the TDLN in mediating the Abscopal Effect. Citation Format: Zachary S. Buchwald, Tahseen H. Nasti, Christiane S. Eberhardt, Andreas Wieland, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K. Khan. Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the Abscopal Effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 526.
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abstract 526 tumor draining lymph node irradiation reduces tumor infiltrating stem like cd8 t cells and abrogates the Abscopal Effect
Cancer Research, 2019Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, David H. Lawson, Walter J. Curran, Rafi Ahmed, Andreas Wieland, Christiane S Eberhardt, Mohammad K. KhanAbstract:Purpose: PD-1 and PD-L1 antagonists are efficacious because cancer induces T-cell exhaustion via upregulation of PD-L1 and persistent antigen exposure. Our lab, has shown that the proliferative burst following αPD-L1 therapy of exhausted CD8+PD-1+T-cells is restricted to a “stem-like” CD8+T-cell subset in a murine chronic viral infection model. The role of these stem-like CD8+T-cells in malignancies and whether these cells respond to other immuno-stimulation including radiotherapy (RT) is unknown. RT’s immuno-stimulation includes acting as an in-situ vaccine by liberating cryptic tumor neo-antigens, generating a potent anti-tumor CD8+T-cell response, synergizing with αPD-1/L1 and leading to control at distant sites of disease outside the radiation field (Abscopal Effect). In initial studies, we found these stem-like CD8+T-cells in B16F10 tumors and at high frequencies in the tumor-draining lymph nodes (TDLN) of immunocompetent mice. Here, we investigated: (1) the impact of tumor-directed RT on this stem-like CD8+T-cell population in the tumor and TDLN in the context of an Abscopal response, and (2) due to the high frequency of stem-like CD8+T-cells in the TDLN, whether depletion of lymphocytes from the TDLN via RT influenced the Abscopal Effect. Experimental Design: We developed a preclinical model of oligo-metastatic melanoma to evaluate the role of stem-like CD8+ T-cells and the TDLN in the Abscopal Effect. This was done with unilateral tumor-directed RT with or without TDLN-directed RT. This was also done in the presence and absence of αPD-L1. Results: Tumor-directed RT improved local tumor control and induced an Abscopal response with a concomitant increase in tumor infiltrating tumor-specific stem-like CD8+T-cells. Tumor-specific stem-like CD8+T-cells were also observed in the TDLN of tumors on both sides. Importantly, the tumor-directed RT increased tumor-specific T-cell proliferation in the TDLNs bilaterally despite only being targeted at one tumor. Given this robust proliferative response and the high frequency of stem-like CD8+T-cells in the TDLN, we next evaluated the role of the TDLN in mediating the Abscopal Effect. We found that the Abscopal Effect is impaired if the TDLN is lymphocyte depleted with TDLN-directed RT in the presence or absence of αPD-L1. Additionally, the tumor-directed RT mediated increase in stem-like T-cells in the irradiated and unirradiated tumor was abrogated with TDLN-directed RT. Conclusion: Our results demonstrate slowed distant tumor growth following irradiation of a local site and that this correlates with an increase in tumor-infiltrating stem-like CD8+T-cells which is reduced with TDLN-directed RT. These data suggest a critical role for both the stem-like CD8+T-cells and the TDLN in mediating the Abscopal Effect. Citation Format: Zachary S. Buchwald, Tahseen H. Nasti, Christiane S. Eberhardt, Andreas Wieland, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K. Khan. Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the Abscopal Effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 526.
Sandra Demaria – One of the best experts on this subject based on the ideXlab platform.
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Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect.
Trends in immunology, 2018Co-Authors: Maria E. Rodriguez-ruiz, Silvia C. Formenti, Claire Vanpouille-box, Ignacio Melero, Sandra DemariaAbstract:Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor Effects manifesting as regression of tumors outside of the irradiated field (Abscopal Effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic Effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic Effects.
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Using immunotherapy to boost the Abscopal Effect
Nature Reviews Cancer, 2018Co-Authors: Wilfred Ngwa, Omoruyi Credit Irabor, Jonathan D. Schoenfeld, Jürgen Hesser, Sandra Demaria, Silvia C. FormentiAbstract:The Abscopal Effect, which is the regression of metastatic cancer at distant sites during radiotherapy, is somewhat rare but can be promoted by immunotherapy. This Opinion article describes emerging concepts and limitations of using a combination of radiotherapy and immunotherapy to boost the Abscopal Effect. More than 60 years ago, the Effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the Abscopal Effect (from ‘ab scopus’, that is, away from the target). The Abscopal Effect has been connected to mechanisms involving the immune system. However, the Effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust Abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost Abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the Abscopal Effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.
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Using immunotherapy to boost the Abscopal Effect
Nature reviews. Cancer, 2018Co-Authors: Wilfred Ngwa, Omoruyi Credit Irabor, Jonathan D. Schoenfeld, Jürgen Hesser, Sandra Demaria, Silvia C. FormentiAbstract:More than 60 years ago, the Effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the Abscopal Effect (from ‘ab scopus’, that is, away from the target). The Abscopal Effect has been connected to mechanisms involving the immune system. However, the Effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust Abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost Abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the Abscopal Effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.