Oncoimmunology最新文献

Sertraline and indatraline are two antidepressants that function as serotonin reuptake inhibitors and have demonstrated promising anticancer potential, although their precise mechanisms of action remain unclear. Both compounds trigger cholesterol accumulation within lysosomes followed by lysosomal membrane permeabilization, ultimately leading to the activation of immunogenic cell death (ICD). This, in turn, triggers a T cell-mediated adaptive immune response that facilitates significant tumor control.

BCMA-directed CAR-T therapies have shown promising results in multiple myeloma (MM). However, patients continue to relapse. T cell exhaustion with increased TIGIT expression is a resistance mechanism which was confirmed in CAR-T cells from ARI0002h trial, an academic CAR-T developed in our institution. We aimed to analyze the impact of blocking TIGIT on the efficacy of ARI0002h. We used three different strategies to block TIGIT: (1) Addition of an external blocking anti-TIGIT-antibody (Ab), (2) Modify ARI0002h into a 4^th generation CAR-T, named ARITIGIT, capable of secreting a soluble TIGIT-blocking scFv and (3) TIGIT knock-out in ARI0002h using CRISPR/Cas9. Each strategy was evaluated in vitro and in vivo. Adding a TIGIT-blocking Ab to ARI0002h improved in vitro cytotoxicity, but failed to enhance mice survival. The new 4^th generation CAR-T, ARITIGIT, was also unable to achieve better survival outcomes despite favoring the in vivo model by using a myeloma cell line with high expression of the TIGIT ligand PVR. Interestingly, when mice were challenged with a second infusion of tumor cells, mimicking a relapse model, a trend for improved survival with ARITIGIT was observed (p = 0.11). Finally, TIGIT-knock-out on ARI0002h (KO-ARI0002h) using CRISPR/Cas9 showed similar in vitro activity to ARI0002h. In an in vivo stress model, TIGIT KO-ARI0002h prolonged survival (p = 0.02). However, this improvement was not significant compared to ARI0002h (p = 0.07). This study failed to demonstrate a significant benefit of TIGIT-blockade on ARI0002h cells despite using three different approaches, suggesting that targeting a single immune checkpoint may be insufficient.

The annual ImmunoRad Conference has established itself as a recurrent occasion to explore the possibility of combining radiation therapy (RT) and immunotherapy (IT) for clinical cancer management. Bringing together a number of preclinical and clinical leaders in the fields of radiation oncology, immuno-oncology and IT, this annual event fosters indeed essential conversations and fruitful exchanges on how to address existing challenges to expand the therapeutic value of RT-IT combinations. The 8th edition of the ImmunoRad Conference, which has been held in October 2024 at the Weill Cornell Medical College of New York City, highlighted exciting preclinical and clinical advances at the interface between RT and IT, setting the stage for extra progress toward extended benefits for patients with an increasing variety of tumor types. Here, we critically summarize the lines of investigation that have been discussed at the occasion of the 8th Annual ImmunoRad Conference.

Adoptive cell therapy and the use of monoclonal antibodies are two therapeutic modalities implemented in the treatment of multiple myeloma (MM). In this study, we combined the anti-CD38 therapeutic mAb daratumumab with different types of NK cells, leveraging the antibody-dependent cell-mediated cytotoxicity (ADCC) performed by these immune cells. Daratumumab was initially combined with activated and expanded NK cells (eNK), resulting in significant cytotoxic activity against human MM cell lines. As an alternative model to minimize the variability among donors of NK cells, the NK92 cell line was used, which showed greater cytotoxic activity than eNK cells against MM cell lines. However, since NK92 cells lacked CD16 receptor expression, they could not be used in combination with mAbs. To circumvent this, we performed a CD16 transfection on NK92 cells, generating the stable NK92-CD16 cell line. These cells were tested in combination with daratumumab against human MM cell lines with excellent results under various conditions, such as 2D and 3D cultures, even at very low effector-to-target ratios. NK92-CD16 cells were then tested in the presence of daratumumab against plasma cells from MM patients, with anti-myeloma activity even against cells from relapsed patients. In vivo experiments using MM xenografts or intravenous injection of MM cells in NGS mice, followed by treatment with NK92-CD16 cells in the presence or absence of daratumumab showed tumor regressions, especially in the second model, with nearly complete elimination of the MM cells when NK92-CD16 cells were combined with daratumumab.

Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has demonstrated consistent clinical efficacy in treating advanced melanoma and other "hot" tumors. However, it has shown limited success in "cold" tumors like glioblastoma. We present the successful treatment of a rapidly progressing glioblastoma patient with TILs expanded using a defined cytokine combination of IL-2, IL-15, and IL-21. The patient received lymphodepletion with cyclophosphamide one day pre-TIL infusion, followed by a single dose of IL-2 post-transfer. Complete tumor regression was observed after two TIL infusions administered two weeks apart. The TIL products were enriched for CD8⁺ T-cells and demonstrated specific lysis of the autologous tumor cell line. Transcriptomic analysis of tumor biopsies post-TIL infusion revealed increased expression of genes associated with immunological synapse formation and T-cell effector function, correlating with the patient's clinical outcome. T-cell receptor (TCR) next-generation sequencing of the infused TILs and post-treatment tumor biopsies confirmed the infiltration and expansion of TIL-derived clonotypes within the tumor microenvironment. CD8⁺ T-cell clonotypes exhibited robust tumor migration and expansion, while CD4⁺ T-cells showed limited tumor infiltration. In conclusion, TILs expanded with IL-2/IL-15/IL-21 represent a promising therapeutic approach for glioblastoma, overcoming traditional challenges posed by the tumor microenvironment and achieving significant clinical outcomes.

Antibody-drug conjugates (ADCs) enable targeted delivery of cytotoxic payload to cancer cells. Here, we characterized the mode of action of the ADC patritumab deruxtecan, which is a monoclonal antibody specific for Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3, best known as HER3) coupled to the topoisomerase-I inhibitor DXd. Patritumab deruxtecan decreased viability and induced the relocation of calreticulin fused to green fluorescent protein (CALR-GFP) to the periphery of human osteosarcoma U2OS cells engineered to express HER3 but not in their parental counterparts only expressing the CALR-GFP biosensor. Patritumab deruxtecan as well as its payload DXd induced various traits of immunogenic cell death (ICD) including antibody detectable calreticulin membrane exposure, exodus of high mobility group protein B1 (HMGB1), as well as the release of ATP into cell culture supernatants. Moreover, DXd causes rapid inhibition of DNA-to-RNA transcription, which is a key predictor for ICD. Mouse cancer cells treated with DXd were able to vaccinate syngeneic immunocompetent mice against tumor challenge. Tumor-free mice developed immune memory that led to the rejection of syngeneic tumors after rechallenge. In conclusion, patritumab deruxtecan is equipped with a cytotoxic payload that induces hallmarks of ICD in vitro and elicits antitumor immunity in vivo.

PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. Accordingly, PT-112 is an authentic immunogenic cell death (ICD) inducer and synergizes with immune checkpoint inhibitors in preclinical models of mammary and colorectal carcinoma. Moreover, PT-112 monotherapy has led to durable clinical responses, some of which persisting after treatment discontinuation. Mitochondrial outer membrane permeabilization (MOMP) regulates the cytotoxicity and immunogenicity of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells to test whether genetic alterations affecting MOMP influence PT-112 activity. As previously demonstrated, PT-112 elicited robust antiproliferative and cytotoxic effects against TS/A cells, which were preceded by the ICD-associated exposure of calreticulin (CALR) on the cell surface, and accompanied by the release of HMGB1 in the culture supernatant. TS/A cells responding to PT-112 also exhibited eIF2α phosphorylation and cytosolic mtDNA accumulation, secreted type I IFN, and exposed MHC Class I molecules as well as the co-inhibitory ligand PD-L1 on their surface. Acute cytotoxicity and HMGB1 release caused by PT-112 in TS/A cells were influenced by MOMP competence. Conversely, PT-112 retained antiproliferative effects and its capacity to drive type I IFN secretion as well as CALR, MHC Class I and PD-L1 exposure on the cell surface irrespective of MOMP defects. These data indicate a partial involvement of MOMP in the mechanisms of action of PT-112, suggesting that PT-112 is active across various tumor types, including malignancies with MOMP defects.

Aclarubicin (also called aclacinomycin A) is an antineoplastic from the anthracycline class that is used in China and Japan but not in Europe nor in the USA. Aclarubicin induces much less DNA damage than the classical anthracyclines doxorubicin, daunorubicin, epirubicin, idarubicin, and the anthracene mitoxantrone, but is equally effective in inhibiting DNA-to-RNA transcription and in eliciting immunogenic stress in malignant cells. Accordingly, aclarubicin lacks the DNA damage-associated cardiotoxicity that is dose-limiting for classical anthracyclines. Conversely, aclarubicin is at least as potent as other anthracyclines in inducing immunogenic cell death (ICD), which is key for the mode of action of efficient chemotherapeutics. This combination of reduced toxicity and equivalent ICD-stimulatory activity may explain why, as compared to other anthracyclines, aclarubicin is particularly efficient against acute myeloid leukemia. As a result, we advocate for clinical studies seeking to replace the anthracyclines used in Western medicine by aclarubicin-like compounds. Such clinical studies should not only embrace hematological malignancies but should also concern solid cancers, including those in which ICD-inducing chemotherapies are followed by immunotherapies targeting the PD-1/PD-L1 interaction.

Mature tertiary lymphoid structures (TLSs) are immune aggregates associated with immune checkpoint blockade (ICB) responses in various cancers, yet their role in chemoimmunotherapy response in head and neck squamous cell carcinoma (HNSCC) remains unclear. By analyzing TCGA-HNSC transcriptomic data and pathology slides, we identified an immune subtype enriched in TLSs, predominantly in HPV-positive tumors, which correlated with favorable immunotherapy response. Single-cell and spatial transcriptomics further revealed distinct TLS compositions, with mature TLSs enriched in germinal center B cells, follicular helper T cells, and resident memory CD8 T cells, while immature TLSs contained FCRL4+ B cells and peripheral helper T cells. Multispectral immunohistochemistry, flow cytometry, and ELISA validated these findings. Notably, neoadjuvant chemoimmunotherapy promoted mature TLS formation. These results suggest that TLS maturity correlates with HPV status and response to anti-PD-1-based chemoimmunotherapy, providing insights for potential therapeutic strategies in HNSCC.