In human blood, 1% to 5% of lymphocytes are ␥␦ T cells; they mostly express the ␥␦ T-cell receptor ( IntroductionThe success of therapeutic monoclonal antibodies (mAbs) in the treatment of cancer can be attributed to their multiple bioactivities. Their mechanism of action combines antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity, antibodydependent phagocytosis, direct cytotoxic activity, and inhibition of receptor signaling. 1 ADCC occurs when cytolytic effector cells expressing a receptor for the Fc region of the IgG class of antibodies (Fc␥ receptors) bind to antibodies on the surface of target cells. In humans, Fc␥ receptors comprise CD16 (Fc␥RIIIA-B), CD32 (Fc␥RIIA-C), and CD64 (Fc␥RI), which all bind the same region on IgG Fc but with low-to-medium (CD16, CD32) or high (CD64) affinities. 2 Several lines of evidence suggest that enhancing ADCC induced by therapeutic mAbs may directly improve their clinical efficacy. First, in mice bearing xenografted tumors, the efficacy of the therapeutic mAbs rituximab (RTX) and trastuzumab (TTZ) relies upon cell-surface expression of Fc␥R. 3 Second, ADCC is essential for the clinical efficacy of RTX in B-cell lymphoma patients and depends on the affinity of Fc␥RIIIA for the IgG. 4,5 Third, optimizing the affinity of RTX, TTZ, and alemtuzumab (ALZ) for Fc␥RIIIA increases their ADCC and their efficacy in preclinical and clinical studies. [6][7][8] Finally, recruitment and activation of additional cell effectors for ADCC might also enhance the cytolytic activity of anticancer mAbs. 9,10 The cytolytic effector cells involved in ADCC are CD16 ϩ (ie, Fc␥RIIIA)-positive natural killer (NK) cells and other CD8 ϩ cytolytic T lymphocytes, which release perforin through immunologic synapses to kill target cells. In addition, human CD4 Ϫ CD8 Ϫ ␥␦ T cells from peripheral blood might provide an important reservoir of cytolytic effector cells for ADCC. In most humans and nonhuman primate species, the majority of circulating ␥␦ T lymphocytes expresses the V␥9 T-cell receptor, with CD4 Ϫ CD8 Ϫ TCRV␥9 ϩ cells representing 1% to 3% of mononuclear cells. All these cells respond to stimulation with nonpeptide phosphoantigens (PAgs), which are small, phosphorylated metabolites produced by the cholesterol pathway in microbial pathogens and tumor cells. In addition to natural PAgs, the synthetic analog BrHPP 11 selectively stimulates TCRV␥9 ϩ ␥␦ T lymphocytes. PAg-stimulated ␥␦ T cells proliferate, secrete pro-inflammatory cytokines and chemokines, and, most importantly, kill leukemia, lymphoma, and carcinoma cells. 12,13 Several studies involving macaque monkeys 14,15 and clinical studies in cancer patients [16][17][18][19][20][21][22] have demonstrated in vivo the potential of PAg-activated TCRV␥9 ϩ ␥␦ T lymphocytes for cancer immunotherapy.The mechanism by which PAgs stimulate ␥␦ T cell-mediated cancer cell killing is unclear. The number of circulating ␥␦ T lymphocytes increases 50-to 100-fold in humans treated with BrHPP and IL2 (our unpublished observations...

Tumor-specific mutations can generate neoantigens that drive CD8 T cell responses against cancer. Next-generation sequencing and computational methods have been successfully applied to identify mutations and predict neoantigens. However, only a small fraction of predicted neoantigens are immunogenic. Currently, predicted peptide binding affinity for MHC-I is often the major criterion for prioritizing neoantigens, although little progress has been made toward understanding the precise functional relationship between affinity and immunogenicity. We therefore systematically assessed the immunogenicity of peptides containing single amino acid mutations in mouse tumor models and divided them into two classes of immunogenic mutations. The first comprises mutations at a nonanchor residue, for which we find that the predicted absolute binding affinity is predictive of immunogenicity. The second involves mutations at an anchor residue; here, predicted relative affinity (compared with the WT counterpart) is a better predictor. Incorporating these features into an immunogenicity model significantly improves neoantigen ranking. Importantly, these properties of neoantigens are also predictive in human datasets, suggesting that they can be used to prioritize neoantigens for individualized neoantigen-specific immunotherapies.

Down-regulation of PLCγ2 and β-catenin signaling in tumor associated myeloid cells allows for their expansion and tumor growth in mice and humans.

One fourth of women with HER-2+ metastatic breast carcinoma are treated with a combination regimen with trastuzumab, but the frequent resistance to this Ab requires definition of new means to improve its bioactivity. The mechanisms of action of trastuzumab involve several pathways including Ab-dependent cellular cytotoxicity. Because human γδ T lymphocytes mediate Ab-dependent cellular cytotoxicity and can be activated further by phosphoantigens, these cells are prone to improve the efficacy of Abs, as recently demonstrated for CD20+ B cell lymphomas. Whether this concept applies as well with carcinomas remained to be demonstrated in vivo, however. In this study, we asked whether a combination of trastuzumab and phosphoantigen-stimulated γδ lymphocytes increases the efficacy of trastuzumab against HER-2+ breast carcinoma cell lines in vivo. We report that repeated infusions of this combination had a better efficacy than that of trastuzumab alone against HER-2+ mammary carcinoma xenografts in mice. In these models, reduction of tumor growth was observed together with trastuzumab opsonization of HER-2+ cells and tumor infiltration by γδ lymphocytes. In addition in humans, the mammary carcinomas of 27 of 30 patients showed significant γδ T cell infiltrates. Altogether, these findings indicate that combination of trastuzumab and stimulated γδ cells represents a new strategy to improve the efficacy of Herceptin (trastuzumab) in HER-2+ breast cancer.

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Introduction 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.

Exhausted T cells have been described in cancer patients and murine tumor models largely based on their expression of various inhibitory receptors. Understanding of the functional attributes of these cells is limited. Here, we report that among CD8+ T cells in commonly used syngeneic tumor models, the coexpression of inhibitory receptors PD-1, LAG3, and TIM3 defined a group of highly activated and functional effector cells. Coexpression of these receptors further enriched for antigen-specific cells with increased T-cell receptor clonality. Anti–PD-L1 treatment increased the number and activation of these triple-positive CD8+ T cells without affecting the density of PD-1− cells. The intratumoral density of CD8+ T cells coexpressing inhibitory receptors negatively correlated with tumor burden. The density ratio and pretreatment phenotype of CD8+ T cells coexpressing inhibitory receptors was positively correlated with response across a variety of tumor models. Our results demonstrate that coexpression of inhibitory receptors is not a signifier of exhausted T cells, but rather can define a group of activated and functional effector cells in syngeneic tumor models. In the cancer setting, these cells could represent a heterogeneous population of not only exhausted but also highly activated cells responsive to treatment.

The objectives of the study were to determine the frequency of erectile dysfunction (ED) after liver transplantation (LT) and discuss potential risk factors. Of 123 eligible LT men, 98 (79.7%) responded to a questionnaire about sexual function at a mean time posttransplant of 5.4 ± 4.0 years (1.0-21). Erection was evaluated using the five-question international index for erectile function score, and sexual satisfaction by the patient-baseline treatment-satisfaction status (TSS) score. Questions also focused on patient perception of changes overtime. We found that after LT, the proportion of sexually inactive men decreased from 29% to 15% (p = 0.01), but the proportion of men with ED remained unchanged. The absence of sexual activity was associated with pretransplant sexual inactivity (p = 0 Introduction The increase in liver transplantation (LT) procedures over the last years and the increased survival following LT (1) have rendered quality-of-life issues, in particular sexuality, a new challenge of care (2). Erectile dysfunction (ED), defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance is a major domain of male sexuality (3). However, data concerning ED in male LT patients are, so far, limited. Most existing studies have used small samples, nonvalidated questionnaires, have concerned both genders (4-6), or have been published in the non-English literature (4). Moreover, few studies have assessed whether ED is a long-term problem after LT or if ED resolves overtime (5). All in all, risk factors for ED in LT patients are largely unknown. A major problem in determining risk factors in this population is that patients who are candidates for LT oftenhave diabetes (7-11), hypertension (9,11,12), cardiovascular disease (8,9,11) and are affected by alcohol intake and cigarette smoking (13,14) SurveyThe survey was developed at a mean time posttransplant of 5. 4 ± 4.0 years (min-max: 1.0-21; median: 4). The duration of the time between LT and posttransplant survey is summarized in Figure 1. Figure 2D). Sexual satisfaction (TSS score)The