In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment

Abstract

Targeting immune checkpoint receptors has emerged as an effective strategy to induce immune-mediated cancer regression in the subset of patients who have significant pre-existing anti-tumor immunity. For the remainder, effective anti tumor responses may require vaccination. Radiotherapy, traditionally used to achieve local tumor control, has acquired a new role, that of a partner for immunotherapy. Ionizing radiation has pro-inflammatory effects that facilitate tumor rejection. Radiation alters the tumor to enhance the concentration of effector T cells via induction of chemokines, cytokines and adhesion molecules. In parallel, radiation can induce an immunogenic death of cancer cells, promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. Newly generated anti-tumor immune responses have been demonstrated post-radiation in both murine models and occasional patients, supporting the hypothesis that the irradiated tumor can become an in situ vaccine. It is in this role, that radiation can be applied to induce anti-tumor T cells in lymphocyte-poor tumors, and possibly benefit patients who would otherwise fail to respond to immune checkpoint inhibitors. This review summarizes preclinical and clinical data demonstrating that radiation acts in concert with antibodies targeting the immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4), to induce therapeutically effective anti-tumor T cell responses in tumors otherwise non responsive to anti-CTLA-4 therapy.

Keywords: Abscopal effect; Immmune checkpoint; Immunotherapy; Radiation-induced vaccination.

Figure 1. Mechanisms of synergy between radiotherapy and anti-CTLA-4 treatment

Schematic illustration highlighting the critical changes induced by each treatment in the tumor-draining lymph nodes (dLNs) and tumor. Untreated tumors: Priming of T cells in dLN is limited by negative signals delivered by CTLA-4. In the tumor, tumor rejection by CD8 T cells is hampered by low MHC class I and immune-stimulatory ligands (e.g., RAE-1) on tumor cells, and by the immunosuppressive tumor microenvironment, rich in TGFβ, Tregs and tolerogenic DCs. Anti-CTLA-4 treatment: Activation and expansion of tumor-specific T cells in dLNs is improved by blocking CTLA-4-mediated negative signal, but it remains suboptimal in the setting of poorly immunogenic tumors due to low antigen availability and low activation of DC. Clearance of intratumoral CTLA-4^hi Tregs is mediated by anti-CTLA-4 mAb via ADCC if FcγR-expressing myeloid cells are present. At the same time, the pro-motility effects of CTLA-4 ligation hinder the formation of a stable immune synapse between activated CD8 T cells and tumor cells. Radiation: induction of ICD provides tumor antigens and activation signals to DCs, but cross-presentation of tumor-derived antigens to CD8 T cells in dLNs is limited by inhibitory signaling via CTLA-4. Radiation combined with anti-CTLA-4: priming of tumor-specific CD8 T cells is markedly enhanced by complementary effects of radiation and anti-CTLA-4. In addition, activated T cell homing to the tumor is facilitated by increased levels of chemokines (CXCL16 and CXCL10) released by tumor cells in response to radiation. Inside the tumor, co-engagement of TCR and NKG2D on CD8 T cells by radiation-induced MHC-I and RAE-1 allow formation of stable immune synapses with tumor cells. Overall, radiation and anti-CTLA-4 therapy have complementary effects that underlie their synergistic interaction in inducing tumor rejection.