Mutant MHC class II epitopes drive therapeutic immune responses to cancer

Abstract

Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient’s tumour possesses a unique set of mutations (‘the mutanome’) that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient’s individual tumour-specific mutations1. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4+ T cells. Vaccination with such CD4+ immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4+ T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient’s tumour with vaccines produced ‘just in time’.

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

“…Neoantigens are tumor specific antigens created by somatic mutations 26 . We found that all AC-NP formulations, with the exception of mPEG AC-NPs, successfully captured neoantigens 24 (Figure 2c, Supplementary Table 1). Notably, AC-NPs also captured a number of damage associated molecular pattern proteins (DAMPs), a broad class of pro-inflammatory molecules that have been shown to potentiate immune response 27 .…”

“…To determine whether AC-NPs captured tumor-specific antigens, we performed an in silico analysis on our mass spectrometry data to determine if any of the captured proteins contain neoantigens expressed by B16F10 cells 24,25 . Neoantigens are tumor specific antigens created by somatic mutations 26 .…”

“…Importantly, negligible IFN-γ production was observed when T cell populations isolated from PLGA and Mal AC-NP treatment arms were stimulated with splenocyte lysates, indicating that the addition of these AC-NP formulations to standard immunotherapy promotes the production of a cancer specific immune response (Figure 4d; Supplementary Figure 12). To determine if AC-NP improve immunotherapy in an antigen-specific manner, we stimulated T cells isolated from animals undergoing different treatment regimens with neoantigen peptide fragments 24 identified in our mass spectrometry analysis (Actn4, Tubb3, Dag1, and Eef2). We found using flow cytometric analysis that T cells from PLGA and Mal AC-NP treatment arms demonstrate more robust IFN-γ production following neoantigen stimulation.…”

A STING-activating nanovaccine for cancer immunotherapy

“…In contrast, OVA 257-280 -PC7A NP achieved the maximum therapeutic efficacy, where 50% of animals survived over 40 days. In B16-F10 melanoma, we used a cocktail of either tumor associated antigens (Gp100 21-41, Trp1 214-237, Trp2 173-196 ) or neoantigens (Obsl1 T1764M , Kif18b K739N , Def8 R255G ) 26 in PC7A NP (0.5 μg for each peptide, 30 μg polymer). PC7A vaccination significantly slowed the growth of B16F10 tumors over antigen only, PC7A only and non-treated controls (Fig.…”

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

“…Specifically, peptide vaccines derived from MHC class I-restricted tumor antigens offer the promise of inducing robust tumor-specific CD8 + T cell responses 1,2 to promote effective antitumor immunity. 3–6 Unfortunately, the efficacy of class I-restricted peptide vaccines has proven to be limited, 7,8 with overall clinical response rates as low as 3%. 9 Class II CD4 + T cell helper epitopes are also capable of inducing potent antitumor immune responses, 10–13 but peptide vaccines consisting of co-administered class I/II epitopes have also not yet experienced widespread clinical success.…”