Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although ...clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8
T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.
Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating ...cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αβ, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells.
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•Cell transformation expands tissue-resident ILC1ls and ILTC1s•ILC1ls and ILTC1s share a distinct gene expression program•ILC1ls and ILTC1s exhibit potent cytotoxicity against tumor cells•IL-15 deficiency depletes ILC1ls and ILTC1s, resulting in tumor outgrowth
Cell transformation triggers a cancer immunosurveillance mechanism that engages tissue-resident lymphocytes derived from innate, TCRαβ, and TCRγδ lineages.
Innate lymphocytes are integral components of the cellular immune system that can coordinate host defense against a multitude of challenges and trigger immunopathology when dysregulated. Natural ...killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we showed that the cytolytic molecule granzyme C was expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C-expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s. These granzyme C-expressing ILC1s required the transcription factors T-bet and, to a lesser extent, Eomes and support from transforming growth factor-β (TGF-β) signaling for their maintenance in the salivary gland. In a transgenic mouse breast cancer model, depleting ILC1s caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Constitutive activation of STAT5, a transcription factor regulated by IL-15, in granzyme C-expressing ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond "helper-like" lymphocytes.
Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune ...responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.
Tumor cells can be detected and cleared by lymphocytes in a process termed cancer immunosurveillance. However, the contributing cell types had not been fully characterized. Using oncogene-induced ...murine models of epithelial cancer, a recent study showed that cell transformation triggers expansion of tissue-resident lymphocytes derived from innate, T cell receptor (TCR) αβ and TCRγδ lineages. These type-1-like innate lymphoid cells (ILC1ls) and type 1 innate-like T cells (ILTC1s) share a gene expression program distinct from those of conventional lymphocytes, and exhibit cytolytic activities against tumor cells. Further deciphering such a tumor-elicited immunosurveillance mechanism may 1 day be harnessed for novel cancer immunotherapy.
Acute lymphoblastic leukemias (ALLs) are characterized by multistep oncogenic processes leading to cell-differentiation arrest and proliferation. Specific abrogation of maturation blockage ...constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. TLX1/TLX3 abrogation or enforced TCRαβ expression leads to TCRα rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCRα-driven TLX1 expression supports TLX “addiction” in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.
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► TLX1 and TLX3 proteins interact with the ETS1 proto-oncogene in T-ALL ► TLX-ETS1 protein interaction blocks TCRα rearrangement via Enhancer-alpha repression ► TLX inactivation and TCRαβ expression induce redifferentiation and apoptosis ► Sustained TLX expression is required for leukemic transformation.
Cellular transformation induces phenotypically diverse populations of tumour-infiltrating T cells
, and immune checkpoint blockade therapies preferentially target T cells that recognize cancer cell ...neoantigens
. Yet, how other classes of tumour-infiltrating T cells contribute to cancer immunosurveillance remains elusive. Here, in a survey of T cells in mouse and human malignancies, we identified a population of αβ T cell receptor (TCR)-positive FCER1G-expressing innate-like T cells with high cytotoxic potential
(ILTCKs). These cells were broadly reactive to unmutated self-antigens, arose from distinct thymic progenitors following early encounter with cognate antigens, and were continuously replenished by thymic progenitors during tumour progression. Notably, expansion and effector differentiation of intratumoural ILTCKs depended on interleukin-15 (IL-15) expression in cancer cells, and inducible activation of IL-15 signalling in adoptively transferred ILTCK progenitors suppressed tumour growth. Thus, the antigen receptor self-reactivity, unique ontogeny, and distinct cancer cell-sensing mechanism distinguish ILTCKs from conventional cytotoxic T cells, and define a new class of tumour-elicited immune response.
The transcription factor Foxo1 is shown to be involved in the determination of distinct subsets of regulatory T (T.sub.reg) cells, and the differentiation of activated phenotype T.sub.reg cells is ...associated with the repression of the Foxo1-dependent transcriptional program; constitutively active Foxo1 expression triggers depletion of activated T.sub.reg cells in peripheral tissues and leads to CD8 T-cell-mediated autoimmunity and anti-tumour immunity.
Regulatory T (T^sub reg^) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance1-5; yet, excessive T^sub reg^ cell activities suppress ...anti-tumour immune responses6-8. Compared to the resting T^sub reg^ (rT^sub reg^) cell phenotype in secondary lymphoid organs, T^sub reg^ cells in non-lymphoid tissues exhibit an activated T^sub reg^ (aT^sub reg^) cell phenotype9-11. However, the function of aT^sub reg^ cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote T^sub reg^ cell suppression of lymphoproliferative diseases12,13, has an unexpected function in inhibiting aT^sub reg^-cell-mediated immune tolerance in mice. We find that aT^sub reg^ cells turned over at a slower rate than rT^sub reg^ cells, but were not locally maintained in tissues. aT^sub reg^ cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. T^sub reg^-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded T^sub reg^ cell homing to non-lymphoid organs, causing CD8^sup +^ T-cell-mediated autoimmune diseases. Compared to T^sub reg^ cells from healthy tissues, tumour-infiltrating T^sub reg^ cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated T^sub reg^ cells, activate effector CD8^sup +^ T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aT^sub reg^ cells that have a crucial function in suppressing CD8^sup +^ T-cell responses; and the Foxo signalling pathway in T^sub reg^ cells can be titrated to break tumour immune tolerance preferentially.
Regulatory T (T.sub.reg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological selftolerance (1-5); yet, excessive T.sub.reg cell activities suppress ...anti-tumour immune responses (6-8). Compared to the resting T.sub.reg (rT.sub.reg) cell phenotype in secondary lymphoid organs, T.sub.reg cells in nonlymphoid tissues exhibit an activated T.sub.reg (aT.sub.reg) cell phenotype (9-11). However, the function of aT.sub.reg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxol, previously demonstrated to promote T.sub.reg cell suppression of lymphoproliferative diseases (12, 13), has an unexpected function in inhibiting aT.sub.reg-cell-mediated immune tolerance in mice. We find that aT.sub.reg cells turned over at a slower rate than rT.sub.reg cells, but were not locally maintained in tissues. aT.sub.reg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. T.sub.reg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded T.sub.reg cell homing to non-lymphoid organs, causing CD8.sup.+ T-cell-mediated autoimmune diseases. Compared to T.sub.reg cells from healthy tissues, tumour-infiltrating T.sub.reg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated T.sub.reg cells, activate effector CD8.sup.+ T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aT.sub.reg cells that have a crucial function in suppressing CD8.sup.+ T-cell responses; and the Foxo signalling pathway in T.sub.reg cells can be titrated to break tumour immune tolerance preferentially.
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