Paper Reading
01
Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence
Michal Harel, Rona Ortenberg, Siva Karthik Varanasi, et al.
Cell, 5 September 2019
Here these authors utilized SILAC method to study the proteomics of melanoma after responses to immunotherapy. In detail, they investigated molecular mechanisms of positive vs negative responses by comparing the proteome of clinical melanoma samples from patients undergoing either tumor-infiltrating lymphocyte (TIL)-based or anti-programmed death 1 (PD1) immunotherapy. They actually quantified more than 10,300 proteins, among them, 4500 proteins ubiquitously exist across most samples. Interestingly, they found that proteins involved in oxidative phosphorylation and lipid metabolism are dramatically induced in responders in both immunotherapy methods. They further confirmed these findings using CRISP-Cas9 knockouts, indicating lipid metabolism as a key regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation. Therefore, lipid metabolism of tumor cells increases the cytotoxic effects of CD8 T cells. Taken together, their study revealed unique metabolic features of melanoma and the response to TIL or anti-PD-1 immunotherapy.
https://doi.org/10.1016/j.cell.2019.08.012
02
A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients
Antonino Cassotta, Vincent Mikol, Thomas Bertrand, et al.
Nature Medicinevolume 25, pages 1402–1407(2019)
Here these authors extensively studied the side effects of Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, which is used to treat patients with relapsing-remitting multiple sclerosis (MS). However, in around 6%of the cases, persistent neutralizing anti-drug antibodies (ADAs) are induced. Therefore, to really understand the mechanisms of ADA responses, they further performed an in-depth analysis of both B and T cell responses in two patients. In detail, they found the ADA responses are polyclonal and recognizes different epitopes from the NZM. Interestingly, in patients, the analysis of the CD4+ T cell responses, combined with mass spectrometry-based peptidomics, they identified a single immunodominant T cell epitope in the FR2-CDR2 region of theNZM light chain. They next modified the CDR2 region of NZM, which retain its binding toα4 integrins, but was not recognized by CD4 T cells. Overall, they generated a systemic analysis of T-B interaction in ADA responses and provided an approach to design novel deimmunized antibodies.
https://doi.org/10.1038/s41591-019-0568-2
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