Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function.

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.

Systemic immunosuppression depletes peripheral blood regulatory B cells in patients with immune thrombocytopenia.

Regulatory B (Breg) cells are potentially implicated in the pathogenesis of immune thrombocytopenia (ITP). We analysed a prospective cohort of newly diagnosed steroid naïve ITP patients enrolled in the multicentre FLIGHT trial and found that the numbers of Bregs in their peripheral blood were similar to healthy controls. In contrast, Breg numbers were significantly reduced in ITP patients treated with systemic immunosuppression (glucocorticoids or mycophenolate mofetil). We also demonstrate that glucocorticoid treatment impairs Breg interleukin-10 production via an indirect T-cell-mediated mechanism.

Temporal dynamics of normalization reweighting.

For decades, neural suppression in early visual cortex has been thought to be fixed. But recent work has challenged this assumption by showing that suppression can be reweighted based on recent history; when pairs of stimuli are repeatedly presented together, suppression between them strengthens. Here we investigate the temporal dynamics of this process using a steady-state visual evoked potential (SSVEP) paradigm that provides a time-resolved, direct index of suppression between pairs of stimuli flickering at different frequencies (5 and 7 Hz). Our initial analysis of an existing electroencephalography (EEG) dataset (N = 100) indicated that suppression increases substantially during the first 2-5 seconds of stimulus presentation (with some variation across stimulation frequency). We then collected new EEG data (N = 100) replicating this finding for both monocular and dichoptic mask arrangements in a preregistered study designed to measure reweighting. A third experiment (N = 20) used source-localized magnetoencephalography and found that these effects are apparent in primary visual cortex (V1), consistent with results from neurophysiological work. Because long-standing theories propose inhibition/excitation differences in autism, we also compared reweighting between individuals with high versus low autistic traits, and with and without an autism diagnosis, across our three datasets (total N = 220). We find no compelling differences in reweighting that are associated with autism. Our results support the normalization reweighting model and indicate that for prolonged stimulation, increases in suppression occur on the order of 2-5 seconds after stimulus onset.

Glucocorticoid treatment in patients with newly diagnosed immune thrombocytopenia switches CD14++ CD16+ intermediate monocytes from a pro-inflammatory to an anti-inflammatory phenotype.

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T-helper subset distribution and enhanced production of pro-inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T-cell phenotypes. Glucocorticoids (GCs) are commonly used for first-line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++ CD16+ ) in untreated patients with newly diagnosed ITP, with these cells displaying a pro-inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti-inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC-induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy.

Intermediate Monocytes in Acute Alcoholic Hepatitis Are Functionally Activated and Induce IL-17 Expression in CD4+ T Cells.

In humans, the three main circulating monocyte subsets are defined by their relative cell surface expression of CD14 and CD16. They are all challenging to study because their characteristics are strongly context specific, and this has led to a range of conflicting reports about their function, which is especially so for CD14++CD16+ (intermediate) monocytes. Ex vivo cultures are also often confounded by the concomitant use of immunosuppressive drugs. We therefore sought to characterize the phenotype and function of intermediate monocytes in the setting of acute inflammation prior to treatment in a cohort of 41 patients with acute alcoholic hepatitis (AH). Circulating intermediate monocytes were enriched in patients with AH and had an activated phenotype with enhanced expression of CCR2 and CD206 compared with healthy controls. Proinflammatory cytokine expression, including IL-1ß and IL-23, was also higher than in healthy controls, but both classical (CD14++CD16-) and intermediate monocytes in AH were refractory to TLR stimulation. Compared with healthy controls, both AH monocyte subsets had greater phagocytic capacity, enhanced ability to drive memory T cell proliferation in coculture, and skewed CD4+ T cells to express an increased ratio of IL-17/IFN-γ. Furthermore, liver tissue from AH patients demonstrated an enrichment of monocytes including the intermediate subset compared with controls. These data demonstrate that intermediate monocytes are expanded, functionally activated, induce CD4+ T cell IL-17 expression, and are enriched in the liver of patients with AH.

Presence of Spotters Improves Bench Press Performance: A Deception Study.

Sheridan, A, Marchant, DC, Williams, EL, Jones, HS, Hewitt, PA, and Sparks, SA. Presence of spotters improves bench press performance: a deception study. J Strength Cond Res 33(7): 1755-1761, 2019-Resistance exercise is a widely used method of physical training in both recreational exercise and athletic populations. The use of training partners and spotters during resistance exercise is widespread, but little is known about the effect of the presence of these individuals on exercise performance. The purpose of the current study was to investigate the effect of spotter presence on bench press performance. Twelve recreationally trained participants (age, 21.3 ± 0.8 years, height, 1.82 ± 0.1 m, and mass, 84.8 ± 11.1 kg) performed 2 trials of 3 sets to failure at 60% of 1 repetition maximum on separate occasions. The 2 trials consisted of spotters being explicitly present or hidden from view (deception). During the trials, total repetitions (reps), total weight lifted, ratings of perceived exertion (RPE), and self-efficacy were measured. Total reps and weight lifted were significantly greater with spotters (difference = 4.5 reps, t = 5.68, p < 0.001 and difference = 209.6 kg, t = 5.65, p < 0.001, respectively). Although RPE and local RPE were significantly elevated in the deception trials (difference = 0.78, f = 6.16, p = 0.030 and difference = 0.81, f = 5.89, p = 0.034, respectively), self-efficacy was significantly reduced (difference = 1.58, f = 26.90, p < 0.001). This study demonstrates that resistance exercise is improved by the presence of spotters, which is facilitated by reduced RPE and increased self-efficacy. This has important implications for athletes and clients, who should perform resistance exercise in the proximity of others, to maximize total work performed.

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A.

Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses.

Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles that each subset plays in autoimmunity are not well studied. In this study, we show that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype toward intermediate CD14(++)CD16(+) cells, and that this is associated with glucocorticoid therapy. We further demonstrate that CD14(++)CD16(+) monocytes from patients and healthy control donors share a similar cell-surface marker and gene expression profile. Comparison of the effects of intermediate CD14(++)CD16(+) monocytes with classical CD14(++)CD16(-) and nonclassical CD14(+)CD16(++) monocytes revealed that the intermediate CD14(++)CD16(+) subset had an attenuated capacity to promote both naive CD4(+) T cell proliferation and polarization into a Th1 phenotype, and memory CD4(+) T cell proliferation and IL-17 expression. Furthermore, CD14(++)CD16(+) cells inhibit CD4(+) T cell proliferation induced by other monocyte subsets and enhance CD4(+) T regulatory cell IL-10 expression. These data demonstrate the impact of glucocorticoids on monocyte phenotype in the context of autoimmune disease and the differential effects of monocyte subsets on effector T cell responses.

Inhibitory FcγRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity.

A major feature that distinguishes type I from type II anti-CD20 monoclonal antibodies (mAbs) and reduces their therapeutic efficacy is the tendency to internalize from the cell surface. We have shown previously that the extent of internalization correlates with the capacity of type I mAb to simultaneously engage both CD20 and the inhibitory Fcγ receptor, FcγRIIb, in a bipolar configuration. Here, we investigated whether mAbs directed at other B-cell surface receptors also engaged FcγRIIb and whether this interaction promoted internalization. Most mAbs engaged and activated FcγRIIb, with the strength of activation related to the level of mAb bound to the cell surface. However, engagement did not affect internalization of most mAb-ligated receptors, either in cell lines or primary chronic lymphocytic leukemia cells with the exception of CD19 and CD38. Furthermore, at high cell concentrations/density both cis and trans interactions between cell-surface bound mAb and FcγRIIb were evident, but trans interactions did not inhibit type I anti-CD20 mAb-mediated internalization. These data identify that FcγRIIb is engaged by many mAbs in both cis and trans configurations, triggering its activation, but that internalization via FcγRIIb occurs for only a select subset. These findings have implications when designing new antibody-based therapeutics.

Fcγ receptor dependency of agonistic CD40 antibody in lymphoma therapy can be overcome through antibody multimerization.

Immunomodulatory mAbs, led by the anti-CTLA4 mAb ipilimumab, are an exciting new class of drugs capable of promoting anticancer immunity and providing durable control of some tumors. Close analysis of a number of agents has revealed a critical yet variable role for Fcγ receptors in their efficacy. In this article, we reveal that agonistic anti-CD40 mAbs have an absolute requirement for cross-linking by inhibitory FcγRIIB when used systemically to treat established BCL1 syngeneic lymphoma, and therapy is lost when using a mouse IgG2a mAb not cross-linked by FcγRIIB. Furthermore, in FcγRIIB-deficient mice the lymphoma itself can provide FcγRIIB to cross-link anti-CD40 on neighboring cells, and only when this is blocked does therapy fail. The dependence on FcγRIIB for immunostimulatory activity was not absolute, however, because when anti-CD40 mAbs were administered systemically with the TLR3 agonist polyinosinic:polycytidylic acid or were given subcutaneously, activatory FcγR could also provide cross-linking. Using this mechanistic insight, we designed multimeric forms of anti-CD40 mAb with intrinsic FcγR-independent activity that were highly effective in the treatment of lymphoma-bearing mice. In conclusion, FcγR-independent anti-CD40 activation is a viable strategy in vivo. These findings have important translational implications, as humans, unlike mice, do not have IgG that binds strongly to FcγRIIB; therefore FcγR-independent derivatives represent an attractive therapeutic option.

Ingestion of a Nitric Oxide Enhancing Supplement Improves Resistance Exercise Performance.

Mosher, SL, Sparks, SA, Williams, EL, Bentley, DJ, and Mc Naughton, LR. Ingestion of a nitric oxide enhancing supplement improves resistance exercise performance. J Strength Cond Res 30 (12): 3520-3524, 2016-Studies have established that supplementation of nitrate increases nitric oxide which in turn improves exercise performance. The current study aimed to investigate the effects of nitrate ingestion on performance of bench press resistance exercise until failure. Twelve recreationally active (age, 21 ± 2 years, height, 177.2 ± 4.0 cm, weight, 82.49 ± 9.78 kg) resistance-trained men participated in the study. The study used a double-blind, randomized cross-over design, where participants ingested either 70 ml of "BEET It Sport" nitrate shot containing 6.4 millimoles (mmol·L) or 400 mg of nitrate or a blackcurrant placebo drink. Participants completed a resistance exercise session, consisting of bench press exercise at an intensity of 60% of their established 1 repetition maximum (1RM), for 3 sets until failure with 2 minutes rest interval between sets. The repetitions completed, total weight lifted, local and general rate of perceived exertion (RPE), and blood lactate were all measured. The results showed a significant difference in repetitions to failure (p ≤ 0.001) and total weight lifted (p ≤ 0.001). However, there were no significant difference between blood lactate over the 2 trials (p = 0.238), and no difference in Local (p = 0.807) or general (p = 0.420) indicators of fatigue as measured by RPE. This study demonstrates that nitrate supplementation has the potential to improve resistance training performance and work output compared with a placebo.

Immunotherapy targeting inhibitory Fcγ receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization.

Genetic deficiency of the inhibitory Fc receptor, FcγRIIB (CD32b), has been shown to augment the activity of activatory FcγR and promote mAb immunotherapy. To investigate whether mAbs capable of blocking FcγRIIB have similar capacity, we recently generated a panel of specific anti-mouse FcγRIIB mAbs that do not cross-react with other FcRs, allowing us to study the potential of FcγRIIB as a therapeutic target. Previous work revealed a number of these mAbs capable of eliciting programmed cell death of targets, and in the present study we demonstrated their ability to promote target cell phagocytosis. However, in a variety of murine tumor models, anti-FcγRIIB mAbs demonstrated limited therapeutic activity despite optimized treatment regimens. Unexpectedly, we observed that the anti-FcγRIIB mAbs are rapidly and extensively consumed in vivo, both by the tumor and host cells, including B cells, leading to a precipitous loss from the circulation. Closer analysis revealed that the anti-FcγRIIB mAbs become extensively internalized from the cell surface within 24 h in vivo, likely explaining their suboptimal efficacy. Subsequent studies revealed that anti-FcγRIIB mAb immunotherapy was effective when used against FcγRIIB(+) tumors in FcγRIIB(-/-) recipients, indicating that consumption of the mAb by nontumor cells is the primary limitation of these reagents. Importantly, similar rates of internalization were not seen on human target cells, at least in vitro. These studies further highlight the need to determine the propensity of mAb therapeutics to internalize target receptors and also identify potential key differences between human and mouse cells in this respect.

Development and characterisation of monoclonal antibodies specific for the murine inhibitory FcγRIIB (CD32B).

Fc receptors (FcRs) play a key role in regulating and coordinating responses from both innate and adaptive arms of the immune system. The inhibitory Fc gamma receptor II (FcγRIIB; CD32) is central to this regulation with FcγRIIB(-/-) mice demonstrating augmented responses to mAb immunotherapy, elevated incidence and severity of auto-immunity, and increased response to mAb-mediated cancer therapy. To date, these observations have remained unexploited therapeutically, partly through a lack of specific mAb reagents capable of exclusively binding mouse FcγRIIB. Thus almost all of the FcγRIIB-binding mAb currently available, such as 2.4G2, also bind FcγRIII (CD16), and polyclonal reagents have limited availability and are of unproven specificity and avidity, making in vivo manipulation of FcγRIIB impossible. Following an extensive immunisation protocol using FcγRIIB(-/-) mice, we recently produced three unique mAb that are suitable for this purpose. Here we characterise these novel reagents and demonstrate that they fall into two distinct categories; those which cause phosphorylation and subsequent activation of FcγRIIB (agonistic) and those that block receptor phosphorylation (antagonistic). These two types of mAb exhibit different characteristics in a range of biochemical, cellular, and functional assays relevant to FcγRIIB activity and mAb therapy.

Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy.

The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.

The effectiveness of heat preparation and alleviation strategies for cognitive performance: A systematic review.

A range of occupational and performance contexts (e.g. military personnel operations, emergency services, sport) require the critical maintenance of cognitive performance in environmentally challenging environments. Several reviews exist which evaluate the effectiveness of heat preparation strategies to facilitate physical performance. To date, no review has explored the usefulness of heat preparation strategies for cognitive performance. Therefore, this systematic review aimed to evaluate a range of interventions for the maintenance of cognitive performance, during or following active or passive heat exposure. Studies to be included were assessed by two authors reviewing title, abstract, and full-text. Forty articles were identified which met the inclusion criteria. Interventions were categorised into chronic (i.e. acclimation/acclimatisation) and acute strategies (i.e. hydration, cooling, supplementation, psychological). The results indicate that medium-term consecutive heat acclimation may mitigate some cognitive deficits under heat stress, although heat acclimation effectiveness could be influenced by age. Further, pre-cooling appears the most effective cooling method for maintaining cognitive performance under heat stress, although results were somewhat ambiguous. The hydration literature showed that the most effective hydration strategies were those which individualised electrolyte fortified fluid volumes to match for sweat loss. Limited research exploring psychological interventions indicates that motivational self-talk could be facilitative for maintaining cognitive skills following exercise in hot conditions. These findings can be used to help inform strategies for maintaining critical cognitive and decision-making skills in hot environments.

The effect of exercise-induced fatigue and heat exposure on soccer-specific decision-making during high-intensity intermittent exercise.

Global warming and the globalisation of sport has increased the prevalence of sports competitions being held in hot environments. However, there is currently limited research investigating the impact of the heat on soccer-specific decision-making skills during exercise reflective of the physical demands of match-play. Therefore, the effects of heat exposure on physical and soccer-specific decision-making performance, biological markers (i.e., metanephrines), appraisal (i.e., challenge vs. threat) and affective states, during prolonged high-intensity intermittent exercise were investigated. Nine well-trained male soccer players completed a 92-min cycling intermittent sprint protocol (CISP), whilst simultaneously responding to a series of soccer-specific decision-making trials at various time points, in two temperature conditions: hot (32°C, 50%rh) and temperate (18°C, 50%rh). Results showed that decision-making score (p = .030) was impaired in the hot compared to the temperate condition. There was a reduced workload in the second half during the hot condition (p = .016), which coincided with a heightened threat state (p = .007) and more unpleasant feelings (p = .008) experienced in the hot, compared to temperate, condition. Furthermore, plasma normetanephrine (NMET) was higher at half-time (p = .012) and post-CISP (p ≤ .001). Also, plasma metanephrine (MET) was higher post-CISP (p = .009) in the hot compared to temperate condition, reflecting a heightened stress response. Our findings highlight the need for practitioners to consider the detrimental effects heat exposure can have on both physical and decision-making performance when looking to facilitate performance in hot conditions.

Cyclophosphamide depletes tumor infiltrating T regulatory cells and combined with anti-PD-1 therapy improves survival in murine neuroblastoma.

The outcome for children with high-risk neuroblastoma is poor despite intensive multi-modal treatment protocols. Toxicity from current treatments is significant, and novel approaches are needed to improve outcome. Cyclophosphamide (CPM) is a key component of current chemotherapy regimens and is known to have immunomodulatory effects. However, this has not been investigated in the context of tumor infiltrating lymphocytes in neuroblastoma. Using murine models of neuroblastoma, the immunomodulatory effects of low-dose CPM were investigated using detailed immunophenotyping. We demonstrated that CPM resulted in a specific depletion of intratumoral T regulatory cells by apoptosis, and when combined with anti-PD-1 antibody therapy, this resulted in improved therapeutic efficacy. CPM combined with anti-PD-1 therapy was demonstrated to be an effective combinational therapy, with metronomic CPM found to be more effective than single dosing in more resistant tumor models. Overall, this pre-clinical data strongly support clinical evaluation of such combination strategies in neuroblastoma.

Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments.

BACKGROUND: Despite extensive clinical use, the mechanisms that lead to therapeutic resistance to anti-programmed cell-death (PD)-1 monoclonal antibodies (mAbs) remain elusive. Here, we sought to determine how interactions between the Fc region of anti-PD-1 mAbs and Fcγ receptors (FcγRs) affect therapeutic activity and how these are impacted by the immune environment. METHODS: Mouse and human anti-PD-1 mAbs with different Fc binding profiles were generated and characterized in vitro. The ability of these mAbs to elicit T-cell responses in vivo was first assessed in a vaccination setting using the model antigen ovalbumin. The antitumor activity of anti-PD-1 mAbs was investigated in the context of immune 'hot' MC38 versus 'cold' neuroblastoma tumor models, and flow cytometry performed to assess immune infiltration. RESULTS: Engagement of activating FcγRs by anti-PD-1 mAbs led to depletion of activated CD8 T cells in vitro and in vivo, abrogating therapeutic activity. Importantly, the extent of this Fc-mediated modulation was determined by the surrounding immune environment. Low FcγR-engaging mouse anti-PD-1 isotypes, which are frequently used as surrogates for human mAbs, were unable to expand ovalbumin-reactive CD8 T cells, in contrast to Fc-null mAbs. These results were recapitulated in mice expressing human FcγRs, in which clinically relevant hIgG4 anti-PD-1 led to reduced endogenous expansion of CD8 T cells compared with its engineered Fc-null counterpart. In the context of an immunologically 'hot' tumor however, both low-engaging and Fc-null mAbs induced long-term antitumor immunity in MC38-bearing mice. Finally, a similar anti-PD-1 isotype hierarchy was demonstrated in the less responsive 'cold' 9464D neuroblastoma model, where the most effective mAbs were able to delay tumor growth but could not induce long-term protection. CONCLUSIONS: Our data collectively support a critical role for Fc:FcγR interactions in inhibiting immune responses to both mouse and human anti-PD-1 mAbs, and highlight the context-dependent effect that anti-PD-1 mAb isotypes can have on T-cell responses. We propose that engineering of Fc-null anti-PD-1 mAbs would prevent FcγR-mediated resistance in vivo and allow maximal T-cell stimulation independent of the immunological environment.

The Effects of Heat Exposure During Intermittent Exercise on Physical and Cognitive Performance Among Team Sport Athletes.

This study investigated the effects of heat exposure on physical and cognitive performance during an intermittent exercise protocol so as to reflect the incremental fatigue experienced during team sports. Twelve well-trained male team sport players completed an 80-minute cycling intermittent sprint protocol (CISP), alongside computerized vigilance and congruent (i.e., simple) and incongruent (i.e., complex) Stroop tasks of cognitive functioning, in two counterbalanced temperature conditions; hot (32°C[50%rh]) and control (18°C[50%rh]). Incongruent Stroop accuracy declined over time (p = .002), specifically in the second (Mdiff = -3.75, SD = 0.90%, p = .009) and third (Mdiff = -4.58, SD = 1.22%, p = .019) quarters compared to the first quarter of the CISP; but there were no differences between temperature conditions. Congruent Stroop reaction time (RT) was quicker in the second quarter of exercise in the hot condition (M = 561.99, SD = 112.93 ms) compared to the control condition (M=617.80, SD = 139.71 ms; p = .022), but no differences were found for congruent Stroop accuracy nor vigilance measures. Additionally, peak power output was lower during the third quarter of the CISP in the hot condition (M = 861.31, SD = 105.20 W) compared to the control condition (M = 900.68, SD = 114.84 W; p < .001). Plasma normetanephrine and metanephrine concentrations increased from pre- to post-CISP (Mdiff = +616.90, SD = 306.99, p < .001; and Mdiff = +151.23, SD = 130.32, p = .002, respectively), with a marginal interaction suggesting a higher normetanephrine increase from pre- to post-CISP in the hot versus the control condition (p = .070). Our findings suggest that accuracy for more complex decisions suffered during prolonged high-intensity intermittent exercise, perhaps due to exercise-induced catecholamine increases. Athletes may have also reduced physical effort under increased heat exposure, indicating how cognitive performance may be sustained in physically demanding environments.