The Abscopal Effect in the Era of Checkpoint Inhibitors

Abstract

Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from “ab scopus”, that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment’s suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.

Managing Metastatic Melanoma in 2022: A Clinical Review

“…46 Furthermore, the potential systemic reactivation of antitumor immunophenotypes after radiation therapy to targeted lesions, also referred to as the abscopal effect, has provided intriguing yet inconsistent data regarding the synergistic improvements of combining radiation therapy with immune-modulating therapies in patients with metastatic melanoma, for which additional prospective data remain desired. 47…”

T-Cell Repertoire in Tumor Radiation: The Emerging Frontier as a Radiotherapy Biomarker

“…Immune lymphocytes and DC activated within the TME via the RT-induced immunomodulation may spread out via lymphatic and blood vessels and mediate antitumor immunity at distant sites. This abscopal effect is at least partially mediated by TME-derived T cells that have been activated upon recognition of tumor antigens released by the irradiated dying tumor cells and presented to them by DC within the inflammatory milieux of TME mainly consisting of cytokines and DAMPs [ 7 , 32 ] ( Figure 2 ). Alternatively, DC loaded with tumor peptides in the irradiated TME may cross-present these peptides to naïve T cells in the lymph nodes [ 32 ] ( Figure 3 ).…”

“…This abscopal effect is at least partially mediated by TME-derived T cells that have been activated upon recognition of tumor antigens released by the irradiated dying tumor cells and presented to them by DC within the inflammatory milieux of TME mainly consisting of cytokines and DAMPs [ 7 , 32 ] ( Figure 2 ). Alternatively, DC loaded with tumor peptides in the irradiated TME may cross-present these peptides to naïve T cells in the lymph nodes [ 32 ] ( Figure 3 ). In this respect, the abscopal effect may be considered as the result of RT acting as an in situ tumor vaccine.…”

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

“…One of the main final outcomes of the described induction of interferon release is the activation of a subset of Th1 response associated CD11c+, CD8α+ BATF+ dendritic cells (DCs) [ 64 ] that migrate to lymph nodes, where they provoke cross-priming of effector CD8+ T cells that will access either the principal lesion or the non-irradiated distant sites, contributing to tumor eradication [ 65 ].…”

“…The immune cell features within the TME are strongly influenced by the cytokine composition, which is highly impacted by RT. The pro-inflammatory conversion occurring in the TME after irradiation contributes to the engagement of lymphocytes and the improvement in effector T-cell activation [63] One of the main final outcomes of the described induction of interferon release is the activation of a subset of Th1 response associated CD11c+, CD8α+ BATF+ dendritic cells (DCs) [64] that migrate to lymph nodes, where they provoke cross-priming of effector CD8+ T cells that will access either the principal lesion or the non-irradiated distant sites, contributing to tumor eradication [65].…”