scholarly journals Antitumor immunity in dMMR colorectal cancers requires interferon-induced CCL5 and CXCL10

2020 ◽  
Author(s):  
Courtney Mowat ◽  
Shayla R. Mosley ◽  
Afshin Namdar ◽  
Daniel Schiller ◽  
Kristi Baker
Keyword(s):  
T Cells ◽  
Signaling Pathways ◽  
Genomic Instability ◽  
Antitumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Colorectal Cancers ◽  
Critical Component ◽  
Chemokine Production ◽  
Dna Mismatch ◽  
Tumor Killing

SummaryColorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) are heavily infiltrated by CD8+ tumor infiltrating lymphocytes (TILs) and are associated with a better prognosis than the majority of CRCs. The immunogenicity of dMMR CRCs is commonly attributed to abundant neoantigen generation due to their extreme genomic instability. However, lack of neoantigenic overlap between these and other CRCs necessitates study of antigen-independent mechanisms of immune activation by dMMR CRCs in order identify therapeutic strategies for treating MMR proficient CRCs. We show here using organoid cocultures and orthotopic models that a critical component of dMMR CRC’s immunogenicity is the activation and recruitment of systemic CD8+ T cells into the tumor epithelium by overexpression of the chemokines CCL5 and CXCL10. This is dependent on endogenous activation of the cGAS/STING and IFN signaling pathways by the damaged DNA in dMMR CRCs. These signaling pathways remain sensitive to exogenous stimulation in other CRCs, identifying an attractive therapeutic avenue for increasing TIL infiltration into normally immune resistant CRC subtypes. We have thus identified a key neoantigen-independent mechanism that underlies the ability for dMMR CRCs to recruit TILs into the tumor epithelium. Given that TIL recruitment is a prerequisite for effective tumor killing either by the endogenous immune system or in the context of immunotherapies, treatments that activate IFN-induced chemokine-production by tumor cells promise to improve the prognosis of patients with many different CRC subsets.Statement of SignificanceA critical component of antitumor immunity in dMMR CRCs is their ability to recruit T cells into the tumor epithelium as a prerequisite to tumor cell killing. This occurs because their extensive genomic instability leads to endogenous activation of cGAS/STING and overexpression of CCL5 and CXCL10.

Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN–driven CCL5 and CXCL10

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Courtney Mowat ◽  
Shayla R. Mosley ◽  
Afshin Namdar ◽  
Daniel Schiller ◽  
Kristi Baker
Keyword(s):  
T Cells ◽  
Mismatch Repair ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Colorectal Cancers ◽  
Type I ◽  
Type I Ifn ◽  
Dna Mismatch ◽  
Infiltrating Lymphocytes

Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8+ T cells into dMMR CRCs strictly depend on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and type I IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be up-regulated by common chemotherapies in all CRCs, indicating that facilitating CD8+ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs, where local priming can be maximized even in neoantigen-poor CRCs.

scholarly journals Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Jitske van den Bulk ◽  
Els M. E. Verdegaal ◽  
Dina Ruano ◽  
Marieke E. Ijsselsteijn ◽  
Marten Visser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mismatch Repair ◽  
Molecular Subtype ◽  
Tumor Infiltrating Lymphocytes ◽  
Colorectal Cancers ◽  
Cell Reactivity ◽  
Mutation Burden ◽  
Consensus Molecular Subtype ◽  
Infiltrating Lymphocytes

Abstract Background The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers. Methods Whole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material. Results Neoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome. Conclusions We have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group.

scholarly journals Amino acids and RagD potentiate mTORC1 activation in CD8+ T cells to confer antitumor immunity

2021 ◽  
Vol 9 (4) ◽  
pp. e002137
Author(s):  
Yiwen Zhang ◽  
Hongrong Hu ◽  
Weiwei Liu ◽  
Shu-Mei Yan ◽  
Yuzhuang Li ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Antitumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Human Colon Cancer ◽  
Cell Immunity ◽  
Mtorc1 Signaling

BackgroundIn the tumor microenvironment, tumor cells are able to suppress antitumor immunity by competing for essential nutrients, including amino acids. However, whether amino acid depletion modulates the activity of CD8+ tumor-infiltrating lymphocytes (TILs) is unclear.MethodIn this study, we evaluated the roles of amino acids and the Rag complex in regulating mammalian target of rapamycin complex 1 (mTORC1) signaling in CD8+ TILs.ResultsWe discovered that the Rag complex, particularly RagD, was crucial for CD8+ T-cell antitumor immunity. RagD expression was positively correlated with the antitumor response of CD8+ TILs in both murine syngeneic tumor xenografts and clinical human colon cancer samples. On RagD deficiency, CD8+ T cells were rendered more dysfunctional, as demonstrated by attenuation of mTORC1 signaling and reductions in proliferation and cytokine secretion. Amino acids maintained RagD-mediated mTORC1 translocation to the lysosome, thereby achieving maximal mTORC1 activity in CD8+ T cells. Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Finally, combined with antiprogrammed cell death protein 1 antibody, LEU supplementation improved T-cell immunity in MC38 tumor-bearing mice in vivo.ConclusionOur results revealed that robust signaling of amino acids by RagD and downstream mTORC1 signaling were crucial for T-cell receptor-initiated antitumor immunity. The characterization the role of RagD and LEU in nutrient mTORC1 signaling in TILs might suggest potential therapeutic strategies based on the manipulation of RagD and its upstream pathway.

scholarly journals B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8+ tumor-infiltrating lymphocytes

2021 ◽  
Vol 7 (3) ◽  
pp. eaax3160
Author(s):  
Gihoon You ◽  
Yangsoon Lee ◽  
Yeon-Woo Kang ◽  
Han Wook Park ◽  
Kyeongsu Park ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Therapeutic Agent ◽  
Bispecific Antibody ◽  
Cytokine Production ◽  
Tumor Infiltrating Lymphocytes ◽  
Clinical Development ◽  
Infiltrating Lymphocytes ◽  
Dose Limiting Toxicity

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB–dependent antitumor response in hB7-H3–overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ “terminally differentiated” subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB–expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3–positive cancers as monotherapy and combination therapy with PD-1 blockade.

scholarly journals The Central Role of CD4+ T Cells in the Antitumor Immune Response

1998 ◽  
Vol 188 (12) ◽  
pp. 2357-2368 ◽  
Author(s):  
Kenneth Hung ◽  
Robert Hayashi ◽  
Anne Lafond-Walker ◽  
Charles Lowenstein ◽  
Drew Pardoll ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antitumor Immunity ◽  
Cell Types ◽  
Tumor Rejection ◽  
Tumor Killing ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Th1 And Th2 Responses

The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8+ cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.

JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Joseph M. McGraw ◽  
Flavian Thelen ◽  
Eric N. Hampton ◽  
Nelson E. Bruno ◽  
Travis S. Young ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Antitumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Tissue Loss ◽  
Mouse Tumor ◽  
Novel Target ◽  
Adenovirus Receptor ◽  
Infiltrating Lymphocytes

T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule–like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti–PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.

scholarly journals Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors

2005 ◽  
Vol 201 (5) ◽  
pp. 779-791 ◽  
Author(s):  
Ping Yu ◽  
Youjin Lee ◽  
Wenhua Liu ◽  
Thomas Krausz ◽  
Anita Chong ◽  
...  
Keyword(s):  
T Cells ◽  
Late Stage ◽  
Antitumor Immunity ◽  
Tumor Development ◽  
Tumor Infiltrating Lymphocytes ◽  
Interferon Γ ◽  
Tumor Site ◽  
Cd4 Cells ◽  
Murine Fibrosarcoma

Tumor environment can be critical for preventing the immunological destruction of antigenic tumors. We have observed a selective accumulation of CD4+CD25+ T cells inside tumors. In a murine fibrosarcoma Ld-expressing Ag104, these cells made up the majority of tumor-infiltrating lymphocytes at the late stage of tumor progression, and their depletion during the effector phase, rather than priming phase, successfully enhanced antitumor immunity. We show here that CD4+CD25+ T cells suppressed the proliferation and interferon-γ production of CD8+ T cells in vivo at the local tumor site. Blockade of the effects of IL-10 and TGF-β partially reversed the suppression imposed by the CD4+ cells. Furthermore, local depletion of CD4+ cells inside the tumor resulted in a change of cytokine milieu and led to the eradication of well-established highly aggressive tumors and the development of long-term antitumor memory. Therefore, CD4+CD25+ T cells maintained an environment in the tumor that concealed the immunogenicity of tumor cells to permit progressive growth of antigenic tumors. Our study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.

NF-κB–dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity

2021 ◽  
Vol 6 (61) ◽  
pp. eabg3570
Author(s):  
Ghita Ghislat ◽  
Ammar S. Cheema ◽  
Elodie Baudoin ◽  
Christophe Verthuy ◽  
Pedro J. Ballester ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Signaling Pathways ◽  
Antitumor Immunity ◽  
Focal Point ◽  
Cytotoxic T Cells ◽  
Nuclear Factor Κb ◽  
Cytokines And Chemokines ◽  
Ifn Γ

Conventional type 1 dendritic cells (cDC1s) are critical for antitumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the antitumor functions of cDC1s in immunogenic tumors are poorly understood. Using single-cell transcriptomics to examine the molecular pathways regulating intratumoral cDC1 maturation, we found nuclear factor κB (NF-κB) and interferon (IFN) pathways to be highly enriched in a subset of functionally mature cDC1s. We identified an NF-κB–dependent and IFN-γ–regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. By mapping the trajectory of intratumoral cDC1 maturation, we demonstrated the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IFN regulatory factor 1 (IRF1) in cDC1s, resulting in impaired expression of IFN-γ–responsive genes and consequently a failure to efficiently recruit and activate antitumoral CD8+ T cells. Last, we demonstrate the relevance of these findings to patients with melanoma, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development of new diagnostic and therapeutic approaches to improve cancer immunotherapy.

scholarly journals ATPIF1 inactivation promotes antitumor immunity through metabolic reprogramming of CD8+ T cells

2020 ◽  
Author(s):  
Genshen Zhong ◽  
Ying Wang ◽  
Jiaojiao Zhang ◽  
Yichun Wang ◽  
Yuan Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Antitumor Immunity ◽  
Cell Activity ◽  
Tumor Infiltrating Lymphocytes ◽  
Metabolic Reprogramming ◽  
Apoptosis Resistance ◽  
Lewis Lung Cancer ◽  
Cell Immunity

AbstractInduction of CD8+ T cell activity is a promising strategy in the cancer immunotherapy. In this study, we identified ATP synthase inhibitory factor 1 (ATPIF1) as a potential target in the induction of CD8+ T cell immunity against tumor. Inactivation of ATPIF1 gene in mice promoted the antitumor activity of CD8+ T cells leading to suppression of tumor growth of B16 melanoma and Lewis lung cancer. The phenotype was abolished by deletion of CD8+ T cells in the ATPIF1-KO mice. The tumor infiltrating CD8+ T cells exhibited strong activities in the proliferation, effector and memory as revealed by the single cell RNA sequencing results of CD45+ tumor infiltrating lymphocytes (TILs) isolated from the tumors. The CD8+ T cells expressed more antitumor makers in the tumor microenvironment and in coculture with the tumor cells. The cells had a higher level of glycolysis after the T cell receptor-mediated activation as revealed by the targeted metabolomics assay. The cells exhibited an extra activity of oxidative phosphorylation before the activation as indicated by the oxygen consumption rate. The cells gained capacities in the proliferation, apoptosis resistance and mitophagy in the glucose-limiting environment. These data suggest that inhibition of ATPIF1 activity by gene inactivation rewired the energy metabolism of CD8+ T cells to enhance their immune activities to the tumors. ATPIF1 is a potential molecular target in the induction of antitumor immunity through metabolic reprogramming of CD8+ T cells for the cancer immunotherapy.

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