Nakazawa et al. studied the peripheral immune profile of a cohort of patients with advanced solid tumors; 54 patients received anti-PD-(L)1 alone and 50 received anti-PD-(L)1 + anti-CTLA-4. The addition of anti-CTLA-4 was associated with a greater increase in peripheral blood CD4+ TH cell subsets, including Treg and Th17 cells, a higher Th17:Treg ratio, and an unexpected increase in Th17 cell expression of TBET, the key regulator of TH1 cell development. The plasma of recipients of combination therapy exhibited an increase in TH1-associated cytokines, particularly the IFNγ-inducible cytokines iTAC, MIG, and IP-10, but not in Th17, Th2, Treg, or myeloid cell cytokines.
Contributed by Paula Hochman
ABSTRACT: The systemic immunological effects of combining anti-CTLA4 therapy with PD-(L)1 blockade remain incompletely characterized, despite the widespread use of this combination in treating various solid tumors across multiple stages of disease. Herein, we investigated the additive impact of anti-CTLA4 on peripheral immune signatures in patients undergoing PD-(L)1 blockade, using blood samples from a cohort of patients receiving checkpoint inhibitor therapy for advanced solid tumors. We performed in-parallel analysis of peripheral blood mononuclear cells (PBMC) using Cytometry by Time-of-Flight (CyTOF) and plasma cytokines using Luminex immunoassay. Our study cohort included 104 patients, 54 who received anti-PD(L)1 alone and 50 who received anti-PD(L)1 in combination with anti-CTLA4. As compared to single-agent anti-PD(L)1, combination therapy was associated with a greater expansion of CD4+ T helper cell subsets, including Th17 (adjusted p=0.04) and regulatory T cells (Treg) (adjusted p=0.02), after multivariable and multiple testing adjustment. In patients receiving anti-CTLA4, examination of functional marker expression within the Th17 subset revealed an increase in expression of the Th1-related transcription factor TBET (p=0.003). Assessment of the peripheral cytokine signatures showed an increase in Th1-associated cytokines (p=0.002) in recipients of combination anti-PD(L)1 and anti-CTLA4, particularly the IFN_-inducible cytokines MIG (adjusted p=0.05) and IP-10 (adjusted p=0.05). Our results confirm prior reports that anti-CTLA4 therapy is associated with augmentation of Th17 cell subsets, and they also show that anti-CTLA4 may reshape CD4+ T-cell responses through Th17-to-Th1 plasticity, revealing a potential mechanism for enhanced antitumor immunity with broader implications immune modulation in immunotherapy.
Author Info: (1) Johns Hopkins Medicine, Baltimore, MD, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins Med
Author Info: (1) Johns Hopkins Medicine, Baltimore, MD, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins Medicine, Baltimore, MD, United States. (5) Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States. (6) Johns Hopkins Medicine, Baltimore, MD, United States. (7) Johns Hopkins Medicine, United States. (8) Johns Hopkins Medicine, United States. (9) Johns Hopkins School of Medicine, Baltimore, MD, United States. (10) Johns Hopkins Medicine, United States. (11) Johns Hopkins Medicine, Baltimore, MD, United States. (12) Johns Hopkins Medicine, BALTIMORE, MD, United States. (13) Johns Hopkins Medicine, Baltimore, United States. (14) Johns Hopkins Medicine, Baltimore, MD, United States. (15) Johns Hopkins Medicine, Baltimore, MD, United States. (16) Genentech, San Francisco, CA, United States. (17) Genentech, San Francisco, CA, United States. (18) Roche (Switzerland), Basel, Switzerland. (19) Genentech, San Francisco, CA, United States. (20) Roche (Switzerland), Basel, Switzerland. (21) Roche (Switzerland), Basel, Switzerland. (22) Johns Hopkins University, Baltimore, MD, United States. (23) Johns Hopkins University, Baltimore, MD, United States. (24) Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
