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Neoadjuvant CD40 agonism remodels the tumor immune microenvironment in locally advanced esophageal/gastroesophageal junction cancer [scRNA-seq]

ABSTRACT: Sotigalimab (sotiga) is an agonistic anti-CD40 monoclonal antibody that can modulate anti-tumor immune responses. In a clinical trial of sotiga combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction cancer, treatment induced pathologic complete responses in 38% of patients. Using high-dimensional single cell techniques, we found that sotiga dramatically re-modeled both peripheral immune responses and the tumor microenvironment (TME), increasing components of antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with myeloid cell alterations, sotiga primed new T cell clonotypes, increased T cells with enhanced cytotoxic activity, and decreased the frequency of Tregs in the TME. Clinical responses were associated with both baseline and treatment-induced T cell states. These findings indicate that sotiga induces antigen presentation leading to enhanced T cell activation and clinical response, and that the immune composition of the TME at baseline is important in conferring sensitivity to this treatment approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244739 | GEO | 2023/12/11

REPOSITORIES: GEO

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Project description:Background: PD-1 pathway blockade has revolutionized cancer care, but many patients do not durably benefit from these therapies. Novel treatments to engage anti-tumor immunity in this setting are needed. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development; however, recent clinical trials of these agents have not demonstrated efficacy for most patients. Here, we present detailed biomarker analyses of a patient with anti-PD-L1 refractory Merkel cell carcinoma that had a durable (~1 year), abscopal response to ADU-S100 (intralesional STING agonist) combined with anti-PD-1 blockade. Methods: Tumor biopsies and peripheral blood acquired pre- and post-treatment were analyzed with single cell RNA sequencing, 27-color flow cytometry, T cell receptor sequencing and multiplexed immunohistochemistry (mIHC; post treatment tumor specimen only). Critically, cancer-specific CD8 T cells were identified using MHC-I tetramers containing peptides from the Merkel cell polyomavirus (MCPyV), the etiologic agent of this cancer. Cell lines and tumor specimens from 76 patients were used to evaluate STING expression and signaling in MCC. Results: High levels of antigen cancer-specific T cells were observed in the tumor prior to ADU-S100 treatment (12% of T cells recognized an MCPyV epitope). These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1. Following STING agonist treatment, MCPyV-specific CD8 T cells expanded 3-fold with minimal phenotypic changes. An increase in antigen presentation on MCC tumor cells was also observed (1.8% of tumor cells MHC-I positive before treatment, 8.2% after treatment). This was not a result of ADU-S100 acting directly on tumor cells as mIHC analysis of 88 tumor samples confirmed little or no STING expression in tumor cells, but high STING expression on infiltrating immune and stromal cells. Further in vitro studies showed MCPyV-positive MCC cell lines are STING deficient, and ADU-S100 did not induce interferon. Conclusions: Our study suggests that STING agonists act on intratumoral immune cells to release interferons, which upregulate tumor cell antigen presentation and reinvigorate the anti-tumor response from pre-existing cancer-specific T cells. Thus, patients with anti-PD-(L)1-refractory disease showing downregulation of antigen-presentation may benefit from intralesional STING agonists.

Project description:All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) can convey non-self antigens derived from pathogens or mutations to amount T-cell responses. Alterations in tumor-specific antigens – particularly mutation-bearing peptides (neoantigens) presented by MHC — can serve as potent substrates for anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring interferon gamma (IFN-γ) induced alterations to antigen presentation, using a lymphoma cell line. IFN-γ treatment resulted in a set of differentially expressed proteins (2 % of all quantified proteins) including components of antigen presentation machinery or interferon signaling pathways. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells antigen repertoires. Accordingly, by surveying immunopeptides, distinct peptide repertoires were exclusively observed in the IFN-γ induced samples. Furthermore, an additional set of presented peptides distinguished control and the IFN-γ samples by their altered relative abundances including neoantigens. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance should help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.

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Neoadjuvant CD40 agonism remodels the tumor immune microenvironment in locally advanced esophageal/gastroesophageal junction cancer [scRNA-seq]

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