Page 63 - 2014 Printable Abstract Book
P. 63
(S1402) Mechanisms of induction of an active immune microenvironment by tumor radiotherapy.
Sandra Demaria, New York Univ School of Medicine, New York, NY
The success of immune checkpoint inhibitors in inducing tumor regression demonstrates that specific
inhibitory pathways are dominant rate-limiting steps in a significant number of patients with cancer.
However, in the majority of patients tumor rejection is hindered by multiple immunosuppressive
mechanisms present in the tumor microenvironment. Obstacles to immune-mediated tumor control can
be present at both the priming and effector phase of the anti-tumor response, and include defective
function and activation of antigen-presenting cells, defective T cell recruitment and infiltration of tumors,
and defective recognition and killing of cancer cells by T cells. Ionizing radiation therapy (RT) applied
locally to a tumor has multiple effects that can potentially overcome each of these obstacles and generate
an active immune microenvironment, which may be a pre-requisite for response to immune checkpoint
inhibitors. In fact, we have shown in pre-clinical models that RT can convert tumors unresponsive to anti-
CTLA-4 mAb into responsive ones, achieving rejection of the irradiated tumor and non-irradiated
metastases (abscopal effect) and improved survival. Importantly, clinical observations suggest that a
similar synergy between RT and anti-CTLA-4 treatments may be achieved in patients.
To gain insights into the mechanisms of synergy between RT and anti-CTLA-4 treatment, we used our well-
characterized 4T1 mouse model in which anti-CTLA-4 treatment is effective only when combined with RT.
We have identified multiple mechanisms that contribute to the success of this combination, including
enhanced recruitment of activated T cells to the tumor and enhanced immune synapse formation
between CD8 T and tumor cells. In addition, we have recently performed a comprehensive evaluation of
the breadth and depth of the T cell repertoire modulated by treatment using high-throughput sequencing
technology. Results show distinct contributions of RT and anti-CTLA-4 to increasing the number and
clonality of tumor-infiltrating T cells, and changes in clonal representation that are unique to the
combination. Data suggest that RT effectively releases endogenous tumor antigens that prime anti-tumor
T cells, supporting the concept that it can be used as a mean to generate an in situ individualized vaccine.
(S1403) Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances
radiotherapy. Paula D. Bos; George Plitas; Dipayan Rudra; Sue Y. Lee; and Alexander Y. Rudensky
Memorial Sloan Kettering Cancer Center, New York, NY
Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer.
Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in
immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression
through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine
mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3 DTR
knock in mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor
progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to
extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4 + T cells
but not on NK or CD8 + T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did
not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However,
T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall
survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an
autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining
61 | P a g e
Sandra Demaria, New York Univ School of Medicine, New York, NY
The success of immune checkpoint inhibitors in inducing tumor regression demonstrates that specific
inhibitory pathways are dominant rate-limiting steps in a significant number of patients with cancer.
However, in the majority of patients tumor rejection is hindered by multiple immunosuppressive
mechanisms present in the tumor microenvironment. Obstacles to immune-mediated tumor control can
be present at both the priming and effector phase of the anti-tumor response, and include defective
function and activation of antigen-presenting cells, defective T cell recruitment and infiltration of tumors,
and defective recognition and killing of cancer cells by T cells. Ionizing radiation therapy (RT) applied
locally to a tumor has multiple effects that can potentially overcome each of these obstacles and generate
an active immune microenvironment, which may be a pre-requisite for response to immune checkpoint
inhibitors. In fact, we have shown in pre-clinical models that RT can convert tumors unresponsive to anti-
CTLA-4 mAb into responsive ones, achieving rejection of the irradiated tumor and non-irradiated
metastases (abscopal effect) and improved survival. Importantly, clinical observations suggest that a
similar synergy between RT and anti-CTLA-4 treatments may be achieved in patients.
To gain insights into the mechanisms of synergy between RT and anti-CTLA-4 treatment, we used our well-
characterized 4T1 mouse model in which anti-CTLA-4 treatment is effective only when combined with RT.
We have identified multiple mechanisms that contribute to the success of this combination, including
enhanced recruitment of activated T cells to the tumor and enhanced immune synapse formation
between CD8 T and tumor cells. In addition, we have recently performed a comprehensive evaluation of
the breadth and depth of the T cell repertoire modulated by treatment using high-throughput sequencing
technology. Results show distinct contributions of RT and anti-CTLA-4 to increasing the number and
clonality of tumor-infiltrating T cells, and changes in clonal representation that are unique to the
combination. Data suggest that RT effectively releases endogenous tumor antigens that prime anti-tumor
T cells, supporting the concept that it can be used as a mean to generate an in situ individualized vaccine.
(S1403) Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances
radiotherapy. Paula D. Bos; George Plitas; Dipayan Rudra; Sue Y. Lee; and Alexander Y. Rudensky
Memorial Sloan Kettering Cancer Center, New York, NY
Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer.
Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in
immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression
through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine
mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3 DTR
knock in mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor
progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to
extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4 + T cells
but not on NK or CD8 + T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did
not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However,
T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall
survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an
autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining
61 | P a g e
