CD4+ T cell-licensed CD8+ T cells drive immunotherapy response in MHC-I negative MMRd cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE330748 | GEO | 2026/08/10
REPOSITORIES: GEO
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Project description:DNA mismatch repair deficiency (MMRd) occurs in multiple malignancies including 10–15% of colorectal cancers (CRC), where it causes increased tumor mutational burden (TMB) and T cell response. MMRd CRC display multiple mechanisms of immune evasion, yet are highly sensitive to immune checkpoint blockade (ICB), with underlying mechanisms only partially understood. We generated genetically engineered mouse models (GEMM) of hereditary (Lynch syndrome) and sporadic MMRd CRC, and found that accelerated tumorigenesis was accompanied by universal tumor loss of major histocompatibility class I (MHC-I) expression and exclusion of cytotoxic CD8+ T cells, but not helper CD4+ T cells. MHC-I deletion (MHC-IKO) in a syngeneic MMRd CRC model reduced tumor CD8+ but not CD4+ cell infiltrate, and accelerated tumor growth. MMRd MHC-IKO tumors were resistant to anti-PDL1 ICB, but sensitive to anti-PD1 and anti-CTLA4 combination ICB (cICB) with response dependent on both CD4+ and CD8+ T cells, but not γδ-T cells. cICB resistance caused by CD4+ cell depletion was reversed by CD40 agonism, suggesting a mechanism where CD4+ cells license CD8+ cells to kill cancer cells by MHC-I-independent activity. Multimodal analysis revealed that CD4+ T cell help increases the cytotoxic state of CD8+ T cells, potentially lowering their MHC-I-independent activation threshold against cancer cells. Our results underscore the central role of MHC-I loss in tumor immune evasion, and the cooperative role of CD4+ and CD8+ cells in cICB response of MHC-I negative tumors. Our data suggest that MHC-I status may be useful as a biomarker to stratify for ICB monotherapy versus combination therapy.
2026-08-10 | GSE333300 | GEO
Project description:Responses to immune checkpoint blockade (ICB) are variable among mismatch repair-deficient (MMRd) cancers. We completed a phase 2 clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients). Mutation burden was higher in tumors with mutational MMRd compared to epigenetic MMRd; however, within each category of MMRd, mutation burden was not associated with ICB response. Notably, JAK1 mutations did not confer resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of anti-tumor immunity against mutational and epigenetic MMRd cancers. Whereas effector CD8+ T cell responses correlated with regression of mutational MMRd tumors, highly active CD16+ NK cells were associated with ICB-responsive epigenetic MMRd tumors. These data highlight the interplay between tumor-intrinsic and extrinsic factors that influence ICB response.
2022-10-07 | GSE212217 | GEO
Project description:CD4 T cells are thought to help promote anti-tumour responses by ‘licensing’ antigen presenting cells (APCs) that activate CD8 T cells. Conventional type 1 dendritic cells (cDC1s) are responsible for cross-presentation of tumour-derived antigens to CD8 T cells. Prevailing models presume that the cDC1 is licensed by CD4 T cells that are themselves activated by a distinct cDC subset, the cDC2. The recent finding that neoantigens presented by major histocompatibility complex (MHC) class II molecules can promote rejection of tumours that lack MHC class II (MHC-II) surface expression is consistent with an indirect action of CD4 T cells, such as cDC1 licensing. However, no study has directly identified the APC that primes the CD4 T cells responsible for licensing or clearly identified the target of CD4 licensing in vivo. Here, we generated cDC1-specific Cre expressing mouse strain to inactivate or induce expression of MHC-I, MHC-II, or CD40 specifically within the cDC1 lineage. Using a tumour model that relies on CD8 T cells and CD4 T cells for rejection, we discovered that early priming of CD4 T cells against tumour-derived antigens, in contrast to soluble antigens, relied overwhelmingly on the cDC1 and not the cDC2. cDC1 do not simply transport antigen to lymph nodes for processing by cDC2, since lack of MHC-II expression on cDC1 prevented CD4 T cell priming. We also found that CD40 signaling not only affects licensing of cDC1 for CD8 T cell priming, but is also critical for the activation of CD4 T cells. Thus, in the setting of tumour-derived antigens, cDC1 can function as an autonomous platform, capable of priming both CD4 and CD8 T cells and orchestrating their cross-talk required for optimal anti-tumour immunity.
2020-06-11 | GSE152196 | GEO
Project description:CD4+ T cell-licensed CD8+ T cells drive immunotherapy response in MHC-I negative MMRd cancer
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Project description:The central tenet of T cell immune surveillance is that MHC class I and class II molecules present antigens to CD8+ and CD4+ T cells, respectively. Here, we uncover a surprising and previously unrecognized role for MHC class I in modulating CD4+ T cell-mediated immunity. Using multiple in vivo models of allogeneic graft-versus-host disease (GVHD) and tumor immunity, we demonstrate that the absence of MHC class I on target cells significantly increases their susceptibility to CD4+ T cell cytotoxicity. Transcriptomic and functional studies indicate this heightened sensitivity to enhanced ferroptosis of the target cells without affecting the degree of CD4+ T cell activation or inflammatory responses. The experimental results are corroborated utilizing multiple large human transcriptomic and sequencing datasets that suggest a role for CD4+ T cells in enhancing immune checkpoint blocker-mediated responses in patients with melanoma and mismatch repair-deficient (MMRd) colon cancers that have downregulated MHC class I. These findings revise and expand the known role of MHC class I in CD8+ T cell and NK cell immunity and demonstrate a previously unrecognized role in CD4+ T cell-mediated cancer and alloimmunity.
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Project description:Unleashing the immune anti-tumor response through immune checkpoint blockade (ICB) has been successful in treating many solid-tumor malignancies, including metastatic melanoma. When successful, the ICB response can be potent; however, half of patients fail to respond. ICB responsiveness is impacted by the harsh solid tumor microenvironment (TME), which is characterized by metabolic stress. The TME impacts tumor antigenicity, with ICB-responsive melanomas exhibiting increased major histocompatibility complex class I (MHC-I) expression. Further investigation of tumor immunogenicity in the context of the TME may improve cellular therapies. Here, we define and characterize an epigenetic mechanism regulating melanoma antigen presentation driven by prolonged metabolic stress. Murine and human melanoma cell lines were cultured under prolonged metabolic stress, forcing cells to adapt to the absence of glucose. Melanoma cells adapted to the absence of glucose have IFN-gamma-independent increases in MHC-I and an increased sensitivity to T cell-mediated killing. Proteomic analysis revealed dysregulation of histone epigenetic modifiers under prolonged metabolic stress, specifically loss of histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2). EZH2 directly silences gene transcription via catalyzing H3K27me3. Following metabolic adaptation, ChIP-sequencing and ChIP-PCR revealed H3K27me3 loss at genes specific to MHC-I antigen presentation. Prolonged metabolic stress in melanoma cells blunt EZH2 levels and H3K27me3 levels at promoters of genes regulating MHC-I presentation, resulting in elevated MHC-I antigenicity and increased CD8+ T cell killing. This demonstrates potential for EZH2 abundance and mutational status as a prognostic indicators of ICB-responsiveness in metastatic melanoma and supports EZH2 inhibition as adjuvant for immunotherapies
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