01/11/2025
Nature
SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade
Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1-9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10-14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for maximal efficacy in immunologically cold tumours, which respond by increasing PD-L1 expression. Similar correlates of vaccination response are found in humans, including increases in type I interferon, myeloid-lymphoid activation in healthy volunteers and PD-L1 expression on tumours. Moreover, receipt of SARS-CoV-2 mRNA vaccines within 100 days of initiating ICI is associated with significantly improved median and three-year overall survival in multiple large retrospective cohorts. This benefit is similar among patients with immunologically cold tumours. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumour-related antigens are potent immune modulators capable of sensitizing tumours to ICIs.
18/09/2025
Cancer research
Quantitative Cell Type Specific Immunopeptidome Analysis of Macrophage and Tumor Co-evolution Reveals Therapeutic MHC-I Peptides in Glioblastoma
Immune checkpoint inhibitors (ICI) have shown impressive performance in treating several types of solid tumors. However, they have been ineffective in glioblastoma (GBM), in part due to the immunosuppressive tumor microenvironment (TME) created by GBM-associated macrophages (GAMs). To uncover MHC-I peptide antigens for targeted immunotherapy, we performed cell type specific immunopeptidome analysis on primary macrophages and GBM tumor cells in a co-culture system to profile MHC-I associated antigen presentation at the tumor-macrophage interface. Co-culturing tumor cells and macrophages induced increased presentation of peptides derived from proteins associated with cytokine signaling pathways on macrophages and from proteins associated with the Rho GTPase pathway on GBM tumor cells. In vivo expression was validated for a cohort of co-culture-induced GAM or GBM associated peptides selected as potential immunotherapy targets, and an mRNA vaccine was developed encoding six peptides from GAMs and GBM tumor cells. Two doses of vaccination generated an antigen specific immune response, significantly delayed GBM tumor growth, and in some cases eradicated tumors. These results demonstrate the translational potential of co-culture induced MHC peptide antigens as therapeutic targets for GBM/GAM targeting vaccines.
15/12/2022
STAR protocols
Screening self-peptides for recognition by mouse alloreactive CD8+ T cells using direct ex vivo multimer staining
Here, we present a protocol to identify immunogenic self-peptide/allogeneic major histocompatibility complex (MHC) epitopes. We describe the generation of enriched alloreactive CD8+ T cells by priming mice with a skin graft expressing the allogeneic MHC class I molecule of interest, followed by boosting with a liver-specific AAV vector encoding the heavy chain of that donor MHC allomorph. We then use a peptide-exchange approach to assemble a range of peptide-MHC (pMHC) multimers for measuring recognition of the various epitopes by these alloreactive T cells. For complete details on the use and execution of this protocol, please refer to Son et al. (2021).1.
09/11/2024
Journal for immunotherapy of cancer
Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression
Intratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors.We developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms. Data from a large cancer patient cohort was used to study whether NeoAg architecture characteristics found to define tumor immunogenicity in our mouse models are linked to ICB responses in patients with cancer.We demonstrate that concurrent expression and clonality define NeoAg architectures which determine the immunogenicity of individual NeoAg and drive immune evasion of tumors with heterogenous NeoAg expression. Mechanistically, we identified concerted interplays between concurrent T-cell responses induced by cross-presenting dendritic cells (cDC1) mirroring the tumor NeoAg architecture during T-cell priming in the lymph node. Depending on the characteristics and clonality of respective NeoAg, this interplay mutually benefited concurrent T-cell responses or led to competition between T-cell responses to different NeoAg. In tumors with heterogenous NeoAg expression, NeoAg architecture-induced suppression of T-cell responses against branches of the tumor drove immune evasion and caused resistance to ICB. Therapeutic RNA-based vaccination targeting immune-suppressed T-cell responses synergized with ICB to enable control of tumors with subclonal NeoAg expression. A pan-cancer clinical data analysis indicated that competition and synergy between T-cell responses define responsiveness to ICB in patients with cancer.NeoAg architectures modulate the immunogenicity of NeoAg and tumors by dictating the interplay between concurrent T-cell responses mediated by cDC1. Impaired induction of T-cell responses supports immune evasion in tumors with heterogenous NeoAg expression but is amenable to NeoAg architecture-informed vaccination, which in combination with ICB portrays a promising treatment approach for patients with tumors exhibiting high ITH.