Biology subjects

Wolchok, J.

Publications and source records attributed to Wolchok, J..

3 recordsLinked to original sources

bioRxiv2022

Integrative Analysis of Checkpoint Blockade Response in Advanced Non-Small Cell Lung Cancer

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). While our understanding of the biology underlying immune checkpoint blockade in NSCLC is still incomplete, studies to date have established predictive roles for PD-L1 tumor expression and tumor mutational burden (TMB). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up 2 Cancer - Mark Foundation (SU2C-MARK) Cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including: 1) favorable (e.g., ATM altered), and unfavorable (e.g., TERT amplified) genomic subgroups, 2) distinct immune infiltration signatures associated with wound healing (unfavorable) and immune activation (favorable), and 3) a novel de-differentiated tumor-intrinsic subtype characterized by expression of endodermal lineage genes, immune activation, and enhanced response rate. Taken together, results from this cohort extend our understanding of NSCLC-specific predictors, providing a rich set of molecular and immunologic hypotheses with which to further our understanding of the biology of checkpoint blockade in NSCLC.

genomics↗

bioRxiv2021

Heat-inactivated modified vaccinia virus Ankara boosts Th1-biased cellular and humoral immune responses as a vaccine adjuvant by activating the STING-mediated cytosolic DNA-sensing pathway

BackgroundProtein or peptide-based subunit vaccines are promising platforms for combating human cancers and infectious diseases. However, one primary concern regarding subunit vaccines is the relatively weak immune responses induced by proteins or peptides. Therefore, developing novel and effective vaccine adjuvants is critical for the success of subunit vaccines. Modified vaccinia virus (MVA) is a safe and effective vaccine against smallpox and monkeypox. In this study, we explored the potential of heat-inactivated MVA (heat-iMVA) as a novel vaccine adjuvant. MethodsWe co-administered heat-iMVA with a model antigen, chicken ovalbumin (OVA), either intramuscularly or subcutaneously twice, two weeks apart, and analyzed anti-OVA specific CD8+ and CD4+ T cells in the spleens and skin draining lymph nodes (dLNs) and serum anti-OVA IgG1 and IgG2c antibodies. We also compared the adjuvanticity of heat-iMVA with several known vaccine adjuvants, including complete Freunds adjuvant (CFA) and AddaVax, an MF59-like preclinical grade nano-emulsion. In addition, we tested whether co-administration of heat-iMVA plus tumor neoantigen peptides or irradiated tumor cells improves antitumor efficacy in a B16-F10 therapeutic vaccination model. Using Stimulator of Interferon Genes (STING) or Batf3-deficient mice, we evaluated the contribution of the STING pathway and Batf3-dependent CD103+/CD8 DCs in heat-iMVA-induced immunity. ResultsCo-administration of protein- or peptide-based immunogens with heat-iMVA dramatically enhances Th1-biased cellular and humoral immune responses. This adjuvant effect of heat-iMVA is dependent on the STING-mediated cytosolic DNA-sensing pathway, and the antigen-specific CD8+ T cell response requires Batf3-dependent CD103+/CD8+ dendritic cells (DCs). Heat-iMVA infection of bone marrow-derived DCs (BMDCs) promoted antigen cross-presentation, whereas live MVA infection did not. RNA-seq analyses revealed that heat-iMVA is a more potent activator of the STING pathway than live MVA. Additionally, combining tumor neoantigen peptides or irradiated tumor cells with heat-iMVA delayed tumor growth and extended the median survival in B16-F10 therapeutic vaccination models. ConclusionsHeat-iMVA induces type I interferon (IFN) production and antigen cross-presentation via a STING-dependent mechanism in DCs. Co-administration of heat-iMVA with peptide antigen generates strong Th1-biased cellular and humoral immunity. Collectively, our results demonstrate that heat-iMVA is a safe and potent vaccine adjuvant.

immunology↗

bioRxiv2016

Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade

Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that somatic mutation burden is associated with benefit and a hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from a previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of those patients. We found that the predictive accuracy does not increase as analysis narrows from somatic mutation burden to predicted MHC Class I neoantigens, expressed neoantigens, or homology to pathogens. Further, the association between somatic mutation burden and response is only found when examining samples obtained prior to treatment. Neoantigen and expressed neoantigen burden are also associated with response, but neither is more predictive than somatic mutation burden. Neither the previously-described tetrapeptide signature nor an updated method to evaluate neoepitope homology to pathogens were more predictive than mutation burden.

cancer biology↗