Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction

Qiu, Jingya; Xu, Baocheng; Ye, Darwin; Ren, Diqiu; Wang, Shangshang; Benci, Joseph L.; Xu, Yuanming; Ishwaran, Hemant; Beltra, Jean-Christophe; Wherry, E. John; Shi, Junwei; Minn, Andy J.

doi:10.1038/s43018-022-00490-y

Cited by 35 publications

(38 citation statements)

References 43 publications

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“…In addition, the accumulation of IFNγ-producing CD8 + T cells in the TME could be the result of overtly activated clones specific for tumor antigens that contribute to feeding IFNγ to the inflammatory milieu but no longer eliminate tumor cells. Indeed, prolonged IFNγ signaling has been shown to result in tumor progression through the upregulation of inhibitory ligands and receptors, immune cell exhaustion and resistance to immunotherapy [ 40 , 41 , 42 ]. Thus, it is possible that IFNγ production upon NKG2D engagement led to PD-1 upregulation and immune cell exhaustion in the TME, as seen for the human CRC cohort.…”

Section: Discussionmentioning

confidence: 99%

NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer

Curio

Lin

Bromley

et al. 2023

Cancers

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Treating colorectal cancer (CRC) is a major challenge due to the heterogeneous immunological, clinical and pathological landscapes. Immunotherapy has so far only proven effective in a very limited subgroup of CRC patients. To better define the immune landscape, we examined the immune gene expression profile in various subsets of CRC patients and used a mouse model of intestinal tumors to dissect immune functions. We found that the NK cell receptor, natural-killer group 2 member D (NKG2D, encoded by KLRK1) and NKG2D ligand gene expression is elevated in the most immunogenic subset of CRC patients. High level of KLRK1 positively correlated with the mRNA expression of IFNG and associated with a poor survival of CRC patients. We further show that NKG2D deficiency in the Apcmin/+ mouse model of intestinal tumorigenesis led to reduced intratumoral IFNγ production, reduced tumorigenesis and enhanced survival, suggesting that the high levels of IFNγ observed in the tumors of CRC patients may be a consequence of NKG2D engagement. The mechanisms governing the contribution of NKG2D to CRC progression highlighted in this study will fuel discussions about (i) the benefit of targeting NKG2D in CRC patients and (ii) the need to define the predictive value of NKG2D and NKG2D ligand expression across tumor types.

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Section: Discussionmentioning

confidence: 99%

NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer

Curio

Lin

Bromley

et al. 2023

Cancers

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“…In the acute setting, ARF6 recycling of cytokine receptors might enhance CTL-mediated tumor killing. With chronic exposure, IFN and IFN can cause epigenetic changes in cancer cells that lead to acquired resistance to ICB 64 . Thus, more work is needed in understanding how ARF6-mediated endocytic trafficking may regulate inflammatory receptors, modulate the ability of cancer cells to adapt to immune attack and impact the efficacy of immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer

Wee,

Wang,

Wilson

et al. 2023

Preprint

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Adaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB.

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“…161 In this setting, abrogating type I IFN signaling in neoplastic cells mediates beneficial (rather than detrimental) effects by relieving local immunosuppression and restoring PD-1 sensitivity. 161 At least in part, these observations relate to the ability of chronic type I IFN responses to suppress the differentiation of PD-1 sensitive TCF1 + progenitor CD8 + T cells. 162…”

Section: Response To Therapymentioning

confidence: 99%

“…Along similar lines, IFNAR1 expression by both malignant and host cells has been involved in the acquired resistance of mouse fibrosarcoma cells to PD‐1 blockage, via a mechanism that involved accrued NOS2 (but not PD‐L1) expression 138 . Most recently, type I IFN responses in malignant cells have also been associated with an inflammatory memory state linked to a feed‐forward signaling loop promoted by 2′‐5′‐oligoadenylate synthetase 1 (OAS1) expression that is conducive to immune dysfunction and PD‐1 resistance 161 . In this setting, abrogating type I IFN signaling in neoplastic cells mediates beneficial (rather than detrimental) effects by relieving local immunosuppression and restoring PD‐1 sensitivity 161 .…”

Section: Impact Of Type I Ifn On Oncogenesis Tumor Progression and Re...mentioning

confidence: 99%

Type I interferon and cancer

Holicek,

Guilbaud,

Klapp

et al. 2023

Immunological Reviews

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SummaryType I interferon (IFN) is a class of proinflammatory cytokines with a dual role on malignant transformation, tumor progression, and response to therapy. On the one hand, robust, acute, and resolving type I IFN responses have been shown to mediate prominent anticancer effects, reflecting not only their direct cytostatic/cytotoxic activity on (at least some) malignant cells, but also their pronounced immunostimulatory functions. In line with this notion, type I IFN signaling has been implicated in the antineoplastic effects of various immunogenic therapeutics, including (but not limited to) immunogenic cell death (ICD)‐inducing agents and immune checkpoint inhibitors (ICIs). On the other hand, weak, indolent, and non‐resolving type I IFN responses have been demonstrated to support tumor progression and resistance to therapy, reflecting the ability of suboptimal type I IFN signaling to mediate cytoprotective activity, promote stemness, favor tolerance to chromosomal instability, and facilitate the establishment of an immunologically exhausted tumor microenvironment. Here, we review fundamental aspects of type I IFN signaling and their context‐dependent impact on malignant transformation, tumor progression, and response to therapy.

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Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction

Cited by 35 publications

References 43 publications

NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer

NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer

ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer

Type I interferon and cancer

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