Taggart et al. created a clinically relevant melanoma transplantation mouse model with intracranial and extracranial tumors, and found that anti-PD-1/anti-CTLA-4 combination treatment (but not either monotherapy) was efficacious in the brain only in the presence of extracranial tumor and was both NK cell- and CD8+ T cell-dependent. Checkpoint blockade significantly increased the trafficking of peripherally expanded and activated CD8+ T cells to the brain via upregulation of ICAM-1 and VCAM-1, but did not induce proliferation or activation in the intracranial tumor.

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 ( approximately 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.

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9YL, United Kingdom. (2) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. (3) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. (4) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. (5) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. (6) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. (7) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. (8) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. (9) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom. (10) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom; M.Lorger@leeds.ac.uk.

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