Genomics provides powerful tools for the identification of biomarkers for response to immune checkpoint blockade, given their potential to analyze multiple parameters simultaneously in an unbiased manner. This offers the opportunity for genomics- and transcriptomics-based selection of patients for rationally designed therapy with immune checkpoint inhibitors.
We investigated the molecular effects of glucosamine supplements, a popular and safe alternative to nonsteroidal anti-inflammatory drugs, for decreasing pain, inflammation, and maintaining healthy joints. Numerous studies have reported an array of molecular effects after glucosamine treatment. We questioned whether the differences in the effects observed in previous studies were associated with the focus on a specific subproteome or with the use of specific cell lines or tissues. To address this question, global mass spectrometry-and transcription arraybased glucosamine drug profiling was performed on malignant cell lines from different stages of lymphocyte development. We combined global label-free MS-based protein quantitation with an open search for modifications to obtain the best possible proteome coverage. Our data were largely consistent with previous studies in a variety of cellular models. We mainly observed glucosamine induced O-GlcNAcylation/O-GalNAcylation (O-HexNAcylation); however, we also observed global and local changes in acetylation, methylation, and phosphorylation. (4,5). The clinical relevance of GlcN, a dietary supplement used in osteoarthritis patients, is unclear (6). Previous investigations of long-term GlcN administration did not reveal risks or concerns (7), which is also consistent with recent studies (8). However, in recent clinical studies, GlcN oral administration (8) did not demonstrate any benefits, and the concentration used in vitro was not comparable with the levels observed in the plasma in vivo after the oral administration of GlcN, which raised skepticism (8, 9). Therefore,
Neoadjuvant immunotherapy with anti-cytotoxic T lymphocyte–associated protein 4 (CTLA4) + anti–programmed cell death protein 1 (PD1) monoclonal antibodies has demonstrated remarkable pathological responses and relapse-free survival in ~80% of patients with clinically detectable stage III melanoma. However, about 20% of the treated patients do not respond. In pretreatment biopsies of patients with melanoma, we found that resistance to neoadjuvant CTLA4 + PD1 blockade was associated with a low CD4/interleukin-2 (IL-2) gene signature. Ex vivo, addition of IL-2 to CTLA4 + PD1 blockade induced T cell activation and deep immunological responses in anti-CTLA4 + anti-PD1–resistant human tumor specimens. In the 4T1.2 breast cancer mouse model of neoadjuvant immunotherapy, triple combination of anti-CTLA4 + anti-PD1 + IL-2 cured almost twice as many mice as compared with dual checkpoint inhibitor therapy. This improved efficacy was due to the expansion of tumor-specific CD8
+
T cells and improved proinflammatory cytokine polyfunctionality of both CD4
+
and CD8
+
T effector cells and regulatory T cells. Depletion studies suggested that CD4
+
T cells were critical for priming of CD8
+
T cell immunity against 4T1.2 and helped in the expansion of tumor-specific CD8
+
T cells early after neoadjuvant triple immunotherapy. Our results suggest that the addition of IL-2 can overcome resistance to neoadjuvant anti-CTLA4 + anti-PD1, providing the rationale for testing this combination as a neoadjuvant therapy in patients with early-stage cancer.
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