LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.

Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.

FDG PET/CT Imaging 1 Week after a Single Dose of Pembrolizumab Predicts Treatment Response in Patients with Advanced Melanoma.

PURPOSE: Immunologic response to anti-programmed cell death protein 1 (PD-1) therapy can occur rapidly with T-cell responses detectable in as little as one week. Given that activated immune cells are FDG avid, we hypothesized that an early FDG PET/CT obtained approximately 1 week after starting pembrolizumab could be used to visualize a metabolic flare (MF), with increased tumor FDG activity due to infiltration by activated immune cells, or a metabolic response (MR), due to tumor cell death, that would predict response. PATIENTS AND METHODS: Nineteen patients with advanced melanoma scheduled to receive pembrolizumab were prospectively enrolled. FDG PET/CT imaging was performed at baseline and approximately 1 week after starting treatment. FDG PET/CT scans were evaluated for changes in maximum standardized uptake value (SUVmax) and thresholds were identified by ROC analysis; MF was defined as >70% increase in tumor SUVmax, and MR as >30% decrease in tumor SUVmax. RESULTS: An MF or MR was identified in 6 of 11 (55%) responders and 0 of 8 (0%) nonresponders, with an objective response rate (ORR) of 100% in the MF-MR group and an ORR of 38% in the stable metabolism (SM) group. An MF or MR was associated with T-cell reinvigoration in the peripheral blood and immune infiltration in the tumor. Overall survival at 3 years was 83% in the MF-MR group and 62% in the SM group. Median progression-free survival (PFS) was >38 months (median not reached) in the MF-MR group and 2.8 months (95% confidence interval, 0.3-5.2) in the SM group (P = 0.017). CONCLUSIONS: Early FDG PET/CT can identify metabolic changes in melanoma metastases that are potentially predictive of response to pembrolizumab and significantly correlated with PFS.

Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.