The success of immune checkpoint inhibitors in inducing tumor regression has demonstrated that specific inhibitory pathways are dominant rate-limiting steps in a significant number of patients with melanoma and other advanced cancers. 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 at therapeutic doses has multiple effects that can potentially overcome each of these obstacles, and we have shown that RT is synergistic with immunotherapy. In pre-clinical models RT converted 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 [1, 2]. At the effector phase, RT enhanced recruitment of activated T cells to the tumor by induction of chemokines , and enhanced immune synapse formation between CD8 T and tumor cells by induction of NKG2D ligands .
At the priming phase, we have found that RT has the potential to activate T cell responses to endogenous tumor antigens. However, this potential is not achieved without blocking dominant immunosuppressive pathways. Priming by RT is regulated by positive signals generated by RT and negative signals pre-existing in the tumor microenvironment and/or induced by RT. Positive signals include the induction of an immunogenic tumor cell death and of type I interferon, both of which show some dependency on the dose and/or fractionation of RT. Among negative signals that are exacerbated by RT we have identified TGFβ as a master regulator of the ability of RT to prime CD8 T cell responses to multiple epitopes derived from endogenous tumor antigens, including a transcription factor that regulates epithelial to mesenchymal transition and metastasis. Importantly, priming of CD8 T cells to endogenous tumor antigens is also achieved by blocking immune checkpoint receptors CTLA-4 or PD-1 in combination with RT while each of these treatments used alone is ineffective. Importantly, blocking both TGFβ and PD-1 further improves RT-elicited priming of tumor-specific CD8 T cells. Finally, to obtain a more comprehensive understanding of the ability of RT to cause antigenic spread and elicit T cells to a broad range of tumor antigens possibly including mutated neo-antigens, we are studying the TCR repertoire of intratumoral T cells in mice treated with RT and anti-CTLA-4. Initial results show distinct contributions of RT and anti-CTLA-4 to increasing T cell number and clonality, and changes in clonal representation that are unique to the combination.
Overall, data support the concept that RT can be used as a mean to generate an in situ individualized vaccine. We are currently exploring this hypothesis in clinical trials testing the combination of RT and inhibitors of dominant immunosuppressive pathways.
Supported by Department of Defense Breast Cancer Research Program, Breast Cancer Research Foundation, Breast Cancer Alliance, The Chemotherapy Foundation.
1. Demaria, et al 2005. Clin Cancer Res 11: 728-734.
2. Dewan, et al 2009. Clin Cancer Res 15: 5379-5388.
3. Matsumura, et al. 2008. J Immunol 181: 3099-3107.
4. Ruocco, et al 2012. J Clin Invest 122: 3718-3730.
Citation Format: Claire Vanpouille-Box, Karsten Pilones, Silvia Formenti, Sandra Demaria. Partnership of radiotherapy and immunotherapy: A new paradigm in cancer treatment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA04.
- ©2015 American Association for Cancer Research.