Lauss et al. analyzed the tumor cell-intrinsic and immune TME features of human melanoma specimens collected after progression on ICB, and highlighted that anti-CTLA-4 and anti-PD-1 resistance occur through different molecular mechanisms. Genetic alterations in antigen presentation or IFNγ pathway genes accounted for 26% of the cases. Anti-CTLA-4-resistant tumors showed an increased number of expanded TCR clones, along with increased Foxp3+ T cells compared to anti-PD-1-resistant samples. Anti-PD-1-resistant tumors were enriched in MITFlowB2M− dedifferentiated melanoma cells and had fewer, mainly PD1-TCF7-, infiltrating CD8+ T cells.
Contributed by Shishir Pant
ABSTRACT: Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1(+) CD8(+) T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.
Author Info: (1) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (2) Divisio
Author Info: (1) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (2) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (3) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (4) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (5) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (6) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (7) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (8) Division of Molecular Hematology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (9) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Dermatology, Skne University Hospital and Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (10) Division of Surgery, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (11) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Department of Hematology, Oncology and Radiation Physics, Skne University Hospital Comprehensive Cancer Center, 22185, Lund, Sweden. (12) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Surgery, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Department of Surgery, Kristianstad Hospital, 29133, Kristianstad, Sweden. (13) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Translational Cancer Research, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (14) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (15) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (16) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. goran_b.jonsson@med.lu.se. Lund University Cancer Center, LUCC, Lund, Sweden. goran_b.jonsson@med.lu.se.
