Immunothérapie anti-cancéreuse et lymphocytes T-Vgamma9Vdelta2 : statégies contre l'échappement tumoral

Chez l'homme, les lymphocytes T-Vgamma9Vdelta2 stimulés par les phosphoantigènes (PAg), exercent une puissante activité cytolytique anti-tumorale. L'activité de ces lymphocytes est actuellement évaluée dans plusieurs essais cliniques d'immunothérapie anti-cancéreuse. Cependant, certaines tumeurs et leur microenvironnement produisent des molécules immunosuppressives susceptibles de contribuer à l'échappement tumoral. Cette thèse décrit notamment la contribution du TGF-beta dans l'échappement tumoral à ce type d'immunothérapie. Cependant, nous montrons que la combinaison des anticorps monoclonaux thérapeutiques aux lymphocytes T-Vgamma9Vdelta2 activés améliore la cytotoxicité anti-tumorale, et peut également contrecarrer l'effet inhibiteur du TGF-beta. Nous illustrons ce concept de combinaison thérapeutique ciblée avec un modèle de xénogreffe de carcinome mammaire Her2/neu. L'ensemble de ces résultats démontre l'intérêt de telles stratégies thérapeutiques en cancérologie.Phosphoantigen-stimulated human TCR-Vgamma9Vdelta2 gamma eltaT lymphocytes exert a potent antitumor cytolysis. Their activity is currently assessed in several clinical trials of cancer immunotherapies. Some cancers and their microenvironment produce suppressive molecules however, which might contribute to tumor escape. This PhD thesis deals with the contribution of TGF-beta to cancer immunoevasion, and means to avoid it. We show that the combination of therapeutic monoclonal antibodies to lymphocytes activated TCR-Vgamma9Vdelta2 gamma delta T cells improves anti-tumoral immunologically-mediated killing and may counter TGF-beta-mediated immunosuppression. We illustrate this concept of targeted therapeutic combination in a murine model of Her2/neu mammary carcinoma xenografts. Together, our results demonstrate the potential of such therapeutic strategies in cancer

Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer

Tumor–stroma interactions contribute to tumorigenesis. Tumor cells can educate the stroma at primary and distant sites to facilitate the recruitment of heterogeneous populations of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor proliferation. One outstanding question is how the local and distant stroma modulate MDSCs during tumor progression. Down-regulation of β-catenin is critical for MDSC accumulation and immune suppressive functions in mice and humans. Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses β-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its antitumor effects in mice lacking β-catenin in myeloid cells or after depletion of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a correlation between CD15(+) myeloid cells and Dkk1 in pancreatic cancer patients. We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced immune suppression via targeting β-catenin in MDSCs

Immunothérapie anti-cancéreuse et lymphocytes T-Vgamma9Vdelta2 (stratégies contre l'échappement tumoral)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Cancer neoantigens and immunogenicity: mutation position matters

Cancer mutations can elicit protective immunity. Computational methods are critical for selecting these neoantigens for immunotherapy. While significant progress has been made in the field in predicting peptide presentation, our understanding of which mutated peptide is recognized as foreign by T cells remains limited. We used mouse vaccination studies to examine the features of immunogenic neoantigens and demonstrated that the mutation position is an important criterion for predicting neoantigens

Sources of Cancer Neoantigens beyond Single-Nucleotide Variants

The success of checkpoint blockade therapy against cancer has unequivocally shown that cancer cells can be effectively recognized by the immune system and eliminated. However, the identity of the cancer antigens that elicit protective immunity remains to be fully explored. Over the last decade, most of the focus has been on somatic mutations derived from non-synonymous single-nucleotide variants (SNVs) and small insertion/deletion mutations (indels) that accumulate during cancer progression. Mutated peptides can be presented on MHC molecules and give rise to novel antigens or neoantigens, which have been shown to induce potent anti-tumor immune responses. A limitation with SNV-neoantigens is that they are patient-specific and their accurate prediction is critical for the development of effective immunotherapies. In addition, cancer types with low mutation burden may not display sufficient high-quality [SNV/small indels] neoantigens to alone stimulate effective T cell responses. Accumulating evidence suggests the existence of alternative sources of cancer neoantigens, such as gene fusions, alternative splicing variants, post-translational modifications, and transposable elements, which may be attractive novel targets for immunotherapy. In this review, we describe the recent technological advances in the identification of these novel sources of neoantigens, the experimental evidence for their presentation on MHC molecules and their immunogenicity, as well as the current clinical development stage of immunotherapy targeting these neoantigens

Erectile dysfunction in end-stage liver disease men.

International audienceINTRODUCTION: In men, erectile dysfunction (ED) is an important issue. Data concerning ED in men with end-stage liver disease (ESLD) is limited, and the risk factors for ED in this population are still unknown. AIMS: To determine the prevalence, timescale, and risk factors for ED in ESLD patients candidates to liver transplantation. METHODS: Patients candidates for a liver transplantation were asked to participate in a mailed survey about sexual function. Among the 123 eligible men, 98 (84%) agreed to complete the questionnaire. MAIN OUTCOME MEASURES: The quality of erection was evaluated using the five-item International Index of Erectile Function (IIEF-5) score, and satisfaction for sexuality, using the patient-baseline Treatment-Satisfaction Scale (TSS) score. Other questions also focused on patient perception of changes over time. RESULTS: On the overall population, 28 patients (29%) were nonsexually active. Among the 70 patients who were sexually active, 52 patients (74%) had ED. Regarding the development of ED, 50% of the patients perceived that a deterioration of erectile function occurred within the six previous months. The absence of sexual activity was more frequent in hepatitis B or C patients (P = 0.02). The risk factors for ED were alcohol intake (P = 0.03), tobacco use (P = 0.03), and cardiovascular disease (P = 0.004). The significant risk factors for having a low TSS score were having viral hepatitis (P = 0.01), and cardiovascular disease (P = 0.01). CONCLUSION: Population of men with ESLD who are candidates for a liver transplantation is characterized by a high frequency of lack of sexual activity, and by a high prevalence of ED and should be targeted by interventions to improve sexual functioning. These preliminary data need further validation in prospective trial using more comprehensive questionnaires

Emerging Concepts for the Treatment of Hematological Malignancies with Therapeutic Monoclonal Antibodies

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Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies

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Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors.

TGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFβ signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFβ and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFβ/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFβ therapy efficacy. Our data suggest that TGFβ works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state