Rolig and Peng et al. identified mouse tumor models with high (LAG3hi) or low (LAG3lo) frequencies of LAG3+ lymphocytes. While LAG3lo mice were sensitive to anti-PD-1, LAG3hi mice were anti-PD-1-resistant, but showed increased sensitivity with the addition of anti-LAG3; this effect was dependent on CD8+ T cells and was enhanced with the depletion of CD4+ T cells. Further, in LAG3hi mice, responses correlated with Treg phenotype plasticity, with improved responses in mice with expanded populations of unstable Tregs. A similar correlation was observed in anti-PD-1 + anti-LAG3-treated patients with metastatic melanoma.
Contributed by Lauren Hitchings
ABSTRACT: Immune checkpoint blockade (ICB) has revolutionized cancer treatment; however, many patients develop therapeutic resistance. We previously identified and validated a pretreatment peripheral blood biomarker, characterized by a high frequency of LAG-3(+) lymphocytes, that predicts resistance in patients receiving anti-PD-1 (aPD-1) ICB. To better understand the mechanism of aPD-1 resistance, we identified murine tumor models with a high LAG-3(+) lymphocyte frequency (LAG-3(hi)), which were resistant to aPD-1 therapy, and LAG-3(lo) murine tumor models that were aPD-1 sensitive, recapitulating the predictive biomarker we previously described in patients. LAG-3(hi) tumor-bearing mice were sensitive to aPD-1 + anti-LAG-3 (aLAG-3) therapy, and this benefit was CD8(+) T cell dependent. The efficacy of combination therapy was enhanced in LAG-3(hi) (but not LAG-3(lo)) mice with depletion of CD4(+) T cells. Furthermore, responses to aPD-1 + aLAG-3 correlated with regulatory T cell (T(reg)) phenotypic plasticity in LAG-3(hi) mice, suggesting a specific role for T(regs) in response to aPD-1 + aLAG-3 treatment. Using T(reg) fate-tracking Foxp3(GFP-Cre-ERT2) _ ROSA(YFP) reporter mice, we demonstrated that expanded populations of unstable T(regs) correlated with improved response to combination therapy in LAG-3(hi) mice. Complementing these preclinical data, an increased proportion of unstable T(regs) also correlated with higher response rate and improved survival after aPD-1 + aLAG-3 therapy in a cohort of patients with metastatic melanoma (n = 117). These data indicate that T(reg) phenotypic plasticity affects aPD-1 + aLAG-3 responsiveness, which may represent a biomarker to aid patient selection and a rational therapeutic target for a subset of PD-1-refractory patients.
Author Info: (1) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Earle A. Chil
Author Info: (1) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (4) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (5) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (6) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (7) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (8) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (9) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (10) Deck Bio, Cambridge, MA 02139 USA. (11) Immuno-Oncology & Combinations Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA. (12) Immuno-Oncology & Combinations Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA. (13) Immuno-Oncology & Combinations Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA. (14) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (15) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (17) University of Connecticut School of Medicine, Farmington, CT 06030, USA. (18) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA.
