(1) Schlenker R (2) Schwalie PC (3) Dettling S (4) Huesser T (5) Irmisch A (6) Mariani M (7) Martínez Gómez JM (8) Ribeiro A (9) Limani F (10) Herter S (11) Yángüez E (12) Hoves S (13) Somandin J (14) Siebourg-Polster J (15) Kam-Thong T (16) de Matos IG (17) Umana P (18) Dummer R (19) Levesque MP (20) Bacac M
Using scRNAseq, Schlenker and Schwalie et al. analyzed peripheral blood cells and cells infiltrating tumors surgically resected from 22 patients with stage III–IV metastatic melanoma who subsequently received CPI therapy. CPI responders exhibited high levels of circulating classical and tumor-infiltrating monocytes, which preferentially transitioned to M1-like macrophages in tumors. In CPI responders, myeloid–T/NK cell interactions were proinflammatory and supported T cell priming and effector activities. In CPI non-responders, myeloid–T/NK cell interactions were immunosuppressive, and CD8+ TILs tended to express stress-, hypoxia-, and apoptosis-related genes.
Contributed by Paula Hochman
(1) Schlenker R (2) Schwalie PC (3) Dettling S (4) Huesser T (5) Irmisch A (6) Mariani M (7) Martínez Gómez JM (8) Ribeiro A (9) Limani F (10) Herter S (11) Yángüez E (12) Hoves S (13) Somandin J (14) Siebourg-Polster J (15) Kam-Thong T (16) de Matos IG (17) Umana P (18) Dummer R (19) Levesque MP (20) Bacac M
Using scRNAseq, Schlenker and Schwalie et al. analyzed peripheral blood cells and cells infiltrating tumors surgically resected from 22 patients with stage III–IV metastatic melanoma who subsequently received CPI therapy. CPI responders exhibited high levels of circulating classical and tumor-infiltrating monocytes, which preferentially transitioned to M1-like macrophages in tumors. In CPI responders, myeloid–T/NK cell interactions were proinflammatory and supported T cell priming and effector activities. In CPI non-responders, myeloid–T/NK cell interactions were immunosuppressive, and CD8+ TILs tended to express stress-, hypoxia-, and apoptosis-related genes.
Contributed by Paula Hochman
BACKGROUND: The treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms. METHODS: We performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III-IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed. FINDINGS: CPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8(+) T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and apoptosis-related gene expression. Consistently, predicted non-responder-enriched myeloid-T/natural killer cell interactions were primarily immunosuppressive, while responder-enriched interactions were supportive of T cell priming and effector function. CONCLUSIONS: Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response. FUNDING: This research was funded by Roche Pharma Research and Early Development.
Author Info: (1) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. Electronic address: ramona.schlenker@roche.com. (2) Roche Innovation Cent
Author Info: (1) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. Electronic address: ramona.schlenker@roche.com. (2) Roche Innovation Center Basel, pRED, Basel, Switzerland. Electronic address: petra.schwalie@roche.com. (3) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (4) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (5) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (6) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (7) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (8) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (9) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (10) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (11) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (12) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (13) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (14) Roche Innovation Center Basel, pRED, Basel, Switzerland. (15) Roche Innovation Center Basel, pRED, Basel, Switzerland. (16) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (17) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (18) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (19) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (20) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland.
Citation: Med 2024 Apr 4 Epub04/04/2024
