Anti–PD-1/anti–CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking

Abstract

<p id="d7423752e274">Brain metastases are an unmet clinical need with high frequency in melanoma patients. With immune checkpoint inhibitors targeting programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) becoming a frontline therapy in melanoma, it is critical to understand how this therapy works in the “immune-specialized” brain microenvironment. Our study shows that in the absence of extracranial tumor, melanoma tumors growing in the brain escape anti–PD-1/anti–CTLA-4 therapy. A synergy between immune checkpoint inhibition and extracranial tumor is required to put a break on brain metastases by enhancing CD8 ⁺ T cell recruitment to the brain via peripheral expansion of effector cells and upregulation of T cell entry receptors on tumor blood vessels. Augmentation of these processes could be explored to enhance the efficacy of immunotherapy in brain metastases. </p><p class="first" id="d7423752e280">Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the “immune specialized” brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8 ⁺ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8 ⁺ T cells were required for intracranial anti–PD-1/anti–CTLA-4 efficacy. Rather than enhancing CD8 ⁺ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8 ⁺ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8 ⁺ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8 ⁺ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti–PD-1/anti–CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer. </p>