Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses

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Science Immunology  09 Apr 2021:
Vol. 6, Issue 58, eabg0117
DOI: 10.1126/sciimmunol.abg0117

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Order of immunotherapy matters

Immune checkpoint blockade is clinically successful in various cancer types, yet many treated patients recur; thus, determining effective combination therapies that induce systemic antitumor immunity is crucial. Immune checkpoint blockade combined with local radiation can improve antitumor responses, but it remains unclear how the sequence of these therapies alters efficacy. Here, Wei et al. used mouse tumor models to demonstrate that treatment with anti–PD-1 after stereotactic body radiation therapy (SBRT) elicited superior systemic antitumor immunity, abscopal effects, and protection compared with anti–PD-1 given before SBRT. These data correlated to improved intratumoral CD8+ T cell responses and decreased CD8+ T cell death in local and distant tumors. This work provides preclinical rationale for giving anti–PD-1 after SBRT in patients with cancer.


Although radiotherapy has been used for over a century to locally control tumor growth, alone it rarely induces an abscopal response or systemic antitumor immunity capable of inhibiting distal tumors outside of the irradiation field. Results from recent studies suggest that combining immune checkpoint blockades to radiotherapy may enhance abscopal activity. However, the treatment conditions and underlying immune mechanisms that consistently drive an abscopal response during radiation therapy combinations remain unknown. Here, we analyzed the antitumor responses at primary and distal tumor sites, demonstrating that the timing of αPD-1 antibody administration relative to radiotherapy determined the potency of the induced abscopal response. Blockade of the PD-1 pathway after local tumor irradiation resulted in the expansion of polyfunctional intratumoral CD8+ T cells, a decrease in intratumoral dysfunctional CD8+ T cells, expansion of reprogrammable CD8+ T cells, and induction of potent abscopal responses. However, administration of αPD-1 before irradiation almost completely abrogated systemic immunity, which associated with increased radiosensitivity and death of CD8+ T cells. The subsequent reduction of polyfunctional effector CD8+ T cells at the irradiated tumor site generated a suboptimal systemic antitumor response and the loss of abscopal responses. Therefore, this report maximizes the potential synergy between radiotherapy and αPD-1 immunotherapy, information that will benefit clinical combinations of radiotherapy and immune checkpoint blockade.

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