Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies

Abstract

Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti–PD-1 and anti–CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen–specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.

Therapeutic KRAS G12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers

“…An increased presence of exhausted T cells and augmented IFN responses suggest that MRTX treatment has the potential to sensitize these tumors to ICB. Nevertheless, in this immune-resistant model (28), addition of an anti-PD1 antibody (Fig. 7A) or a combination of anti-PD-L1 and anti-LAG-3 antibodies (fig.…”

Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers

“…An increased presence of exhausted T cells and augmented IFN responses suggest that MRTX treatment has the potential to sensitize these tumours to ICB. Nevertheless, in this immune-resistant model ( 28 ), addition of an anti-PD1 antibody (Fig 7A) or a combination of anti-PD-L1 and anti-LAG3 antibodies (Fig S6A) did not improve the response to KRAS G12C inhibition alone, nor did it enhance the TME remodeling driven by KRAS G12C inhibition (Fig 7B). We found that the lack of therapeutic response observed was not due to insufficient antigen presentation by the tumour cells, as re-expression of the epigenetically silenced H2Kb by treatment with the DNA methyltransferase inhibitor Decitabine in these cells did not improve responses to MRTX+PD1 (Fig S6B and S6C).…”

Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1

“…Consistent with this, a recent study reported that CD8 + TILs specific for mRiok1 (the same sequence as the immunogenic short peptide S50 in our study) were present in LLC1 tumors and were expanded after anti-PD-1 or anti-CTLA-4 treatment. Nonetheless, as in our model, a combination of prophylactic mRiok1 vaccination, anti-PD-1, and anti-CTLA-4 also failed to induce a protective anti-tumor response [ 26 ].…”