Cell-dependent Antitumor Immunity Research Articles

Hybrid Membrane-Camouflaged Biomimetic Immunomodulatory Nanoturrets with Sequential Multidrug Release for Potentiating T Cell-Mediated Anticancer Immunity.

Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.

Hybrid Membrane-Camouflaged Biomimetic Immunomodulatory Nanoturrets with Sequential Multidrug Release for Potentiating T Cell-Mediated Anticancer Immunity.

Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.

Intratumoral delivery of the chitin-derived C100 adjuvant promotes robust STING, IFNAR, and CD8+ T cell-dependent anti-tumor immunity

Stimulator of IFN genes (STING) is a promising target for adjuvants utilized in in situ cancer vaccination approaches. However, key barriers remain for clinical translation, including low cellular uptake and accessibility, STING variability necessitating personalized STING agonists, and interferon (IFN)-independent signals that can promote tumor growth. Here, we identify C100, a highly deacetylated chitin-derived polymer (HDCP), as an attractive alternative to conventional STING agonists. C100 promotes potent anti-tumor immune responses, outperforming less deacetylated HDCPs, with therapeutic efficacy dependent on STING and IFN alpha/beta receptor (IFNAR) signaling and CD8+ Tcell mediators. Additionally, C100 injection synergizes with systemic checkpoint blockade targeting PD-1. Mechanistically, C100 triggers mitochondrial stress and DNA damage to exclusively activate the IFN arm of the cGAS-STING signaling pathway and elicit sustained IFNAR signaling. Altogether, these results reveal an effective STING- and IFNAR-dependent adjuvant for in situ cancer vaccines with a defined mechanism and distinct properties that overcome common limitations of existing STING therapeutics.

Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade

BackgroundOvarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor...

Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity.

T cells are master effectors of anti-tumor immunity in cancer. Recent studies suggest that altered lipid metabolism imposed by the tumor microenvironment constrains anti-tumor immunity. However, the tumor-associated lipid species changes that dampen T cell ability to control tumor progression are not fully understood. Here, we plan to clarify the influences of distinctly altered lipid components in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) on T-cell function, aiming to seek lipid metabolic targets for improving T cell anti-tumor effects. Tumor tissues and non-tumor liver from HCC patients were collected for RNA-sequencing, lipid profiling and T cell characterizing, followed by correlation analysis. Additionally, the effects of significantly changed lipid components on anti-tumor potential of T cells were tested by in vitro cell experiments and/or in vivo tumor inoculated model. Altered lipid metabolism coincides with impaired T cell response in HBV-related HCC. Characteristic lipid composition, significantly marked by accumulation of long-chain acylcarnitines (LCACs) and reduction of lysophosphatidylcholines (LPCs), are found in the tumor tissue. Notably, LCACs accumulated are associated with T cells exhaustion and deficient functionality, while LPCs correlate to anti-tumor effects of T cells. In particular, supplement of LPCs, including LPC (20:0) and LPC (22:0), directly promote the activation and IFN-γ secretion of T cells in vitro, and suppress tumor growth in vivo. Our study highlights the distinctly changed lipid components closely related to T cell dysregulation in HCC, and suggests a promising strategy by decreasing LCACs and increasing LPCs for anti-tumor immunotherapy.

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis.

The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D-NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.

Distinct role of CD8 cells and CD4 cells in antitumor immunity triggered by cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir system.

Immune cells can recognize tumor-associated antigens released from dead tumor cells, which elicit immune responses, potentially resulting in tumor regression. Tumor cell death induced by chemotherapy has also been reported to activate immunity. However, various studies have reported drug-induced immunosuppression or suppression of inflammation by apoptotic cells. Thus, this study aimed to investigate whether apoptotic tumor cells trigger antitumor immunity independent of anticancer treatment. Local immune responses were evaluated after direct induction of tumor cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system. The inflammatory response was significantly altered at the tumor site after apoptosis induction. The expression of cytokines and molecules that activate and suppress inflammation simultaneously increased. The HSV-tk/GCV-induced tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors. Therefore, the role of T cells after inducing tumor cell death was explored. CD8 T cell depletion abrogated the antitumor efficacy of apoptosis induction, indicating that tumor regression was mainly dependent on CD8 T cells. Furthermore, CD4 T cell depletion inhibited tumor growth, suggesting the potential role of CD4 T cells in suppressive tumor immunity. Tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion to elucidate this immunological mechanism. Foxp3 and CTLA4, regulatory T-cell markers, decreased. Furthermore, arginase 1, an immune-suppressive mediator induced by myeloid cells, was significantly downregulated. These findings indicate that tumors accelerate CD8 T cell-dependent antitumor immunity and CD4 T cell-mediated suppressive immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy.

Targeting lL-38 triggers γδ T cell-dependent anti-tumor immunity

Abstract The IL-1 family receptor antagonist IL-38 suppresses auto-inflammatory reactions in murine disease models. Given the connection between auto-immunity and anti-tumor immunity, we wondered if targeting IL-38 would affect the latter. The transgenic PyMT mammary carcinoma model was employed to target IL-38 genetically or with a neutralizing antibody. IL-38-deficient (KO) PyMT mice had a markedly delayed tumor growth compared to WT mice, accompanied by increased NK cells, CD8+, NKT, and γδ T cell infiltrates. Accordingly, in human mammary carcinoma, IL-38 expression negatively correlated with infiltrating T cell subsets. This pattern was largely recapitulated with a IL-38-neutralizing antibody, where antibody-treated PyMT WT mice showed a strong decrease in tumor growth compared to IgG control treated animals, accompanied by an increase in CD8+ and γδ T cells. In a therapeutic model of chemoresistance, IL-38 antibody in combination with doxorubicin prevented tumor relapse, which was accompanied by increased in NK cells, CD8+, CD4+, and γδ T cells. To analyze the involvement of γδ T cells, we used γδ-TCR blocking antibody compared to IgG control in IL-38 KO mice. The delay in growth of IL-38 KO PyMT tumors compared to WT PyMT tumors was abolished upon γδ-TCR blockade. This was accompanied by a strong decrease in CD8+ cells upon effective γδ-TCR blockade, suggesting a cross talking between CD8+ and γδ T cells. Whole transcriptome sequencing analysis of PyMT tumors upon IL-38 neutralization and γδ-TCR blockage suggested NOTCH signaling to mediate the link between CD8+ and γδ T cells. Taken together, these results provide evidence for a therapeutic potential of anti-IL-38 antibodies to activate anti-tumor immunity in mammary carcinoma. Supported by a grant from Deutsche Krebshilfe (70114051)

Abstract 6389: Differential role of CD8 cells and CD4 cells in anti-tumor immunity triggered by tumor cell apoptosis using HSVtk/GCV system

Abstract Immune cells can recognize tumor antigens and elicit an adaptive immune response, potentially resulting in tumor regression. Drug-induced dead tumor cells have been reported to enhance anti-tumor immunity, but results are conflicting, possibly due to the immunosuppressive effects of the cytotoxic drugs. To investigate whether apoptotic tumor cells trigger anti-tumor immunity independent of anti-cancer treatment, local immune responses were evaluated after direct induction of tumor cell apoptosis using a herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) system. The inflammatory cytokines IFNγ and IL-12β and anti-inflammatory factor PD-1 and TGFβ1 were upregulated at the tumor site after apoptosis induction. HSV-tk/GCV-induced tumor cell apoptosis resulted in suppression of tumor growth in vivo and promoted the infiltration of CD8 and CD4 T lymphocytes in tumor. To explore the role of T cells after induction of tumor cell death, GCV was administered together with anti-CD8 or anti-CD4 depleting antibodies to syngeneic HSV-tk transfected tumor-bearing mice. CD8 T cell depletion abrogated the anti-tumor efficacy of GCV, indicating that tumor regression was mainly dependent on CD8 T cells. This anti-tumor immunity was enhanced by anti-PD-1 antibody injection. On the contrary, CD4 T cell depletion further inhibited tumor growth than GCV alone, suggesting the potential role of CD4 T cells in suppressive tumor immunity. To elucidate this immunological mechanism, tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion. Foxp3, a regulatory T cell marker, was decreased after CD4 T cell depletion. In addition, Arg1, a marker of immunosuppressive myeloid cells, was significantly downregulated, which was expressed on tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (mMDSCs). Collectively, these findings indicate that tumor cell apoptosis accelerates CD8 T cell-dependent anti-tumor immunity and CD4 T cell-mediated Arg1 production from TAMs and mMDSCs. Citation Format: Sho Umegaki, Hidekazu Shirota, Tomoyuki Iwasaki, Yuki Kasahara, Chikashi Ishioka. Differential role of CD8 cells and CD4 cells in anti-tumor immunity triggered by tumor cell apoptosis using HSVtk/GCV system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6389.

CIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism invitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use invivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth invivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell-dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer

ObjectivesNo immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. Materials and methodsWe used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. ResultsInjection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity. ConclusionAd-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.

An optimized ionizable cationic lipid for brain tumor-targeted siRNA delivery and glioblastoma immunotherapy

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a high mortality rate. Immunotherapy has achieved promising clinical results in multiple cancers, but shows unsatisfactory outcome in GBM patients, and poor drug delivery across the blood-brain barrier (BBB) is believed to be one of the main limitations that hinder the therapeutic efficacy of drugs. Herein, a new cationic lipid nanoparticle (LNP) that can efficiently deliver siRNA across BBB and target mouse brain is prepared for modulating the tumor microenvironment for GBM immunotherapy. By designing and screening cationic LNPs with different ionizable amine headgroups, a lipid (named as BAMPA-O16B) is identified with an optimal acid dissociation constant (pKa) that significantly enhances the cellular uptake and endosomal escape of siRNA lipoplex in mouse GBM cells. Importantly, BAMPA-O16B/siRNA lipoplex is highly effective to deliver siRNA against CD47 and PD-L1 across the BBB into cranial GBM in mice, and downregulate target gene expression in the tumor, resulting in synergistically activating a T cell-dependent antitumor immunity in orthotopic GBM. Collectively, this study offers an effective strategy for brain targeted siRNA delivery and gene silencing by optimizing the physicochemical property of LNPs. The effectiveness of modulating immune environment of GBM could further be expanded for potential treatment of other brain tumors.

Abstract 2101: RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T cell-dependent anti-tumor immunity

Abstract Expanding the utility of immune-based cancer treatments is a clinical challenge due to tumor-intrinsic factors that suppress the immune response. Here we report the identification of tumoral Ring Finger Protein 2 (RNF2), the core subunit of the Polycomb Repressor Complex 1 (PRC1), as a negative regulator of antitumor immunity in various human cancers, including breast cancer. In syngeneic murine models of triple negative breast cancer, we found that deleting genes encoding PRC1 subunits Rnf2 or BMI1 proto-oncogene, polycomb ring finger (Bmi1), or the downstream effector of Rnf2, Remodeling and Spacing Factor 1 (Rsf1), was sufficient by itself to induce durable tumor rejection and establish immune memory by enhancing infiltration and activation of NK and CD4+ T-cells, but not CD8+ T-cells, into the tumor and enabled their cooperativity. These findings uncover an epigenetic reprogramming of the tumor-immune microenvironment which fosters durable antitumor immunity and memory. Citation Format: Zhuo Zhang, Lin Luo, Chuan Xing, Yu Chen, Peng Xu, Mao Li, Ling Zeng, Chao Li, Sadashib Ghosh, Deborah Della Manna, Tim Townes, William J. Britt, Narendra Wajapeyee, Barry P. Sleckman, Zechen Chong, Jianmei Wu Leavenworth, Eddy Yang. RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T cell-dependent anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2101.

Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer.

Sex bias exists in the development and progression of nonreproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8+ T cell-dependent antitumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7/TCF1+ progenitor exhausted CD8+ T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8+ T cells and a pertinent contribution from AR as a direct transcriptional transactivator of Tcf7/TCF1. The T cell-intrinsic function of AR in promoting CD8+ T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8+ T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation

BackgroundRadiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor...

Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3K\u03b1/\u03b2/\u03b4 treatment

Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/β/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, β2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn “cold” tumors into T cell-inflamed ones, paving the way for successful ICT.

CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells

BackgroundWhile stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses...

Fc\u03b3R engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.

Immune Circuits to Shape Natural Killer Cells in Cancer.

Simple SummaryNatural killer (NK) cells are circulating innate lymphocytes endowed with antitumoral functions. NK cells are the innate counterpart of effector T cells and among the first cells responding to infections and tumors. In this review, the immune circuits regulating the NK cell antitumoral functions and the possible strategies to shape natural killing in cancer will be discussed.Natural killer (NK) cells are innate lymphoid cells playing an important role in anti-cancer immunity. NK cells are efficient in controlling the spreading of metastasis but are not very powerful in fighting against primary tumors. The NK cell capability to infiltrate and persist in the tumor microenvironment and to exert their antitumoral functions is often limited by tumor escape mechanisms. These tumor-mediated strategies not only induce NK cell tolerance but also interfere with the NK cell-dependent immune networking. This review will provide an overview of the tumor escape mechanisms impacting NK cells, identify the immune circuits regulating the NK cell-dependent antitumor immunity and revise the emerging therapeutic approaches to unleash NK cells in cancer.

Abstract IA-05: Immune health and intratumoral immune heterogeneity: Barriers to the efficacy of immunotherapy in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) has shown remarkable resistance to immunotherapy including immune checkpoint blockade, vaccines, and other immunomodulatory agents. In cancer, immunosurveillance can be regulated at both the priming and effector phases of an immune response. Based on this reasoning, we investigated a role for the CD40 pathway in mice and humans as a strategy to prime for tumor-reactive T cells. Our studies showed that systemic CD40 activation triggers productive innate immunosurveillance that sensitizes PDAC tumors to chemotherapy but is insufficient to provoke T cell dependent anti-tumor immunity. However, CD40 activation can restore the functional capacity of peritumoral T cells. Consistent with this, PDAC development associates with progressive loss in T cell priming capacity along with a deficiency in circulating dendritic cells. This biology observed in mouse models is mirrored in humans where patients with PDAC show a decrease in circulating dendritic cells and an increase in T cell dysfunction. To overcome these defects in T cell priming and deficiencies in immune health, we studied adoptive transfer of tumor-reactive chimeric antigen receptor (CAR)-modified autologous T cells in patients. Our findings show that the persistence of adoptively transferred T cells is markedly impaired in patients with PDAC compared to hematologic malignancies. In addition, CAR-T cells show limited anti-tumor activity in PDAC. This lack of efficacy has prompted our investigation into the biology of the tumor microenvironment which displays remarkable spatial heterogeneity in immune cell infiltrates. In our studies, we have identified phenotypically distinct cellular communities marked by weak (“cold”) and strong (“hot”) infiltration of T cells. We find that these distinct regions of PDAC tumors are orchestrated by unique immunoregulatory mechanisms with therapeutic implications. Overall, our findings demonstrate that immunological barriers residing both within and outside the tumor microenvironment have the potential to impair the efficacy of immunotherapy in PDAC. In addition, our data suggest that the immunogenicity of PDAC varies spatially throughout tumors raising the likelihood that multiple, distinct mechanisms of immune evasion will need to be circumvented for immunotherapy to produce benefit for most patients. Citation Format: Gregory Beatty. Immune health and intratumoral immune heterogeneity: Barriers to the efficacy of immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-05.