The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Interim Deputy Editor-in-Chief Dr. Sjoerd H. van der Burg.
“Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction” by Jingya Qiu et al
Nature Cancer (2023)
Loss of interferon gamma (IFNy) signaling is a canonical mechanism of resistance to PD-1 blockade, yet persistent interferon signaling also contributes to immunosuppression in viral infections and cancer. Integrating sophisticated multi-omics approaches in published datasets and animal models, Jignya Qiu and colleagues describe a feedforward mechanism in which IFNy-mediated epigenetic remodeling of cancer cells results in sustained suppressed antitumor immunity. Interrogating gene expression data from The Cancer Genome Atlas (TCGA), a signature of interferon-stimulated genes associated with type-I interferon was correlated with impaired cytolytic activity in CD8+ T cells. Strikingly, ATAC-seq data implicated chromatin accessibility as a major driver of expression, and cis-regulatory elements for these genes were enriched for the IRF/2 archetype (non-redundant) motif that is associated with transcription factors regulated by STAT1 and pattern recognition receptors. Mouse models recapitulated the extensive chromatin remodeling associated with checkpoint blockade seen in the TGCA data, with paralogs identified as the top hits. Chronic IFNy stimulation of checkpoint-blockade-susceptible melanoma cells prior to implantation resulted in increased chromatin accessibility in almost one quarter of the enhancer elements that are constitutively active in checkpoint-blockade-resistant tumors, and 21% of enhancers remained active in resistant cells despite knockout of STAT1. When this persistent type-I interferon signaling in resistant cancer cells was blocked by genetic deletion, survival was prolonged in the mice, interactions between dendritic cells and T cells were enhanced, and T cell populations were skewed toward effector-like states.
Why This Matters: These results describe a mechanistic link between interferon gamma signaling in cancer cells and epigenetic changes that suppress T cell activation and function, further highlighting the “double-edged sword” of interferon in cancer. The data provides a rich resource for hypothesis generation for biomarker discovery or therapeutic targeting aimed at predicting and preventing resistance to checkpoint blockade.
“Addressing tumor heterogeneity by sensitizing resistant cancer cells to T cell-secreted cytokines” by Yoshinaga Ito et al
Cancer Discovery (2023)
T cells recognizing and eliminating tumor cells that present peptides on major histocompatibility complex class I (MHC-I) exerts an intense selective pressure that frequently results in silencing or loss of one or more components of the antigen presentation machinery. Noticing surprisingly substantial elimination of MHC-I deficient melanoma by T cells, Yoshinaga Ito and colleagues performed a series of screens, in vitro, and in vivo experiments to identify autophagy and tumor necrosis alpha (TNFa) as pathways that can be targeted to sensitize cancer cells to cytokine-mediated killing by T cells even in the absence of MHC-I. Genetic co-dependency screens identified TNF signaling genes and an autophagy gene as dependent on interferon and TNF receptor genes for perforin- and granzyme-independent killing B2M knockout cells. Knockout of prototypical autophagy and TNF signaling genes in melanoma cells lacking MHC-I as well as model cell lines for triple negative breast cancer and colon cancer resulted in synergistic sensitization to killing by T cell supernatants. In murine models with heterogeneous MHC-I-proficient and MHC-I-deficient tumors, genetic and pharmacologic inhibition of autophagy and TNFa signaling also synergistically enhanced anti-tumor efficacy. Furthermore, tumor antigens released by lysed autophagy- and TNFa-deficient cells were efficiently cross-presented by dendritic cells.
Why This Matters: Loss of MHC expression is a major mediator of resistance to checkpoint blockage. These findings provide preclinical basis for further investigation of interventions targeting autophagy and TNFa signaling to enhance responses to checkpoint inhibition.
“T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants” by Daniel Hirschhorn et al
Cell (2023)
Tumors are heterogeneous and immunoediting by T cells causes outgrowth of clones lacking immunodominant antigens. Observing that antigen-specific adoptively transferred T cells efficiently eliminated tumors with subpopulations of antigen negative cells in mouse models, Daniel Hirschhorn et al reveal a key role for neutrophils in clearing tumors treated with T cell-targeting immunotherapies. Mice implanted with Trp1-expressing B16 tumors are cured following triple therapy consisting of cyclophosphamide conditioning, adoptive transfer of CD4+ Trp1-specific T cells, and an OX40 agonistic antibody. Triple therapy also eliminates heterogeneous tumors with mixed Trp1 expression, even in RAG knockout mice lacking endogenous lymphocytes. Cytokine profiling of the triple therapy-treated heterogeneous tumors revealed a signature characteristic of innate immune cells, specifically high levels of GM-CSF, IL-3, MIP-1a, and MIP-1b, and high numbers of neutrophils undergoing NETosis were visualized infiltrating the tumors by microscopy. In vitro, tumor extracts from treated tumors caused naïve neutrophils to increase killing of Trp1-negative target cells, and neutrophils as well as intact nitric oxide signaling were required for the triple therapy to eliminate heterogeneous tumors in vivo. In checkpoint blockade-responsive mouse models bearing MC38 tumors, depletion of neutrophils markedly reduced the efficacy of anti-PD-1 in combination with anti-CTLA-4. Biopsy samples from human patients treated with anti-CTLA-4 with or without anti-PD-1 as well as patients treated with anti-OX40 in a phase I trial were heavily infiltrated with neutrophils.
Why This Matters: Neutrophils are known to exert pro- and anti-tumor effects, depending on the context. These findings put forth a new model of tumor elimination in which initial killing by antigen-specific T cells is followed by a “clean-up crew” of neutrophils to eliminate antigen-negative tumor cells. Interventions aimed at potentiating neutrophils may potentially be developed to enhance the efficacy of T cell-directed immunotherapies.