The generation of antitumor CD8+ T cell responses requires type I interferon responsiveness in host antigen-presenting cells

It is now little disputed that most if not all cancer cells express antigens that can be recognized by specific CD8(+) T lymphocytes. However, a central question in the field of anti-tumor immunity is why such antigen-expressing tumors are not spontaneously eliminated by the immune system. While in some cases, this lack of rejection may be due to immunologic ignorance, induction of anti-tumor T-cell responses in many patients has been detected in the peripheral blood, either spontaneously or in response to vaccination, without accompanying tumor rejection. These observations argue for the importance of barriers downstream from initial T-cell priming that need to be addressed to translate immune responses into clinical tumor regression. Recent data suggest that the proper trafficking of effector T cells into the tumor microenvironment may not always occur. T cells that do effectively home to tumor metastases are often found to be dysfunctional, pointing toward immunosuppressive mechanisms in the tumor microenvironment. T-cell anergy due to insufficient B7 costimulation, extrinsic suppression by regulatory cell populations, inhibition by ligands such as programmed death ligand-1, metabolic dysregulation by enzymes such as indoleamine-2,3-dioxygenase, and the action of soluble inhibitory factors such as transforming growth factor-beta have all been clearly implicated in generating this suppressive microenvironment. Identification of these downstream processes points to new therapeutic targets that should be manipulated to facilitate the effector phase of anti-tumor immune responses in concert with vaccination or T-cell adoptive transfer.

IMPORTANCE An intraoperative higher level of positive end-expiratory positive pressure (PEEP) with alveolar recruitment maneuvers improves respiratory function in obese patients undergoing surgery, but the effect on clinical outcomes is uncertain. OBJECTIVE To determine whether a higher level of PEEP with alveolar recruitment maneuvers decreases postoperative pulmonary complications in obese patients undergoing surgery compared with a lower level of PEEP. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 2013 adults with body mass indices of 35 or greater and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia. The trial was conducted at 77 sites in 23 countries from July 2014-February 2018; final follow-up: May 2018. INTERVENTIONS Patients were randomized to the high level of PEEP group (n = 989), consisting of a PEEP level of 12 cm H 2 O with alveolar recruitment maneuvers (a stepwise increase of tidal volume and eventually PEEP) or to the low level of PEEP group (n = 987), consisting of a PEEP level of 4 cm H 2 O. All patients received volume-controlled ventilation with a tidal volume of 7 mL/kg of predicted body weight. MAIN OUTCOMES AND MEASURES The primary outcome was a composite of pulmonary complications within the first 5 postoperative days, including respiratory failure, acute respiratory distress syndrome, bronchospasm, new pulmonary infiltrates, pulmonary infection, aspiration pneumonitis, pleural effusion, atelectasis, cardiopulmonary edema, and pneumothorax. Among the 9 prespecified secondary outcomes, 3 were intraoperative complications, including hypoxemia (oxygen desaturation with SpO 2 Յ92% for >1 minute). RESULTS Among 2013 adults who were randomized, 1976 (98.2%) completed the trial (mean age, 48.8 years; 1381 [69.9%] women; 1778 [90.1%] underwent abdominal operations). In the intention-to-treat analysis, the primary outcome occurred in 211 of 989 patients (21.3%) in the high level of PEEP group compared with 233 of 987 patients (23.6%) in the low level of PEEP group (difference, −2.3% [95% CI, −5.9% to 1.4%]; risk ratio, 0.93 [95% CI, 0.83 to 1.04]; P = .23). Among the 9 prespecified secondary outcomes, 6 were not significantly different between the high and low level of PEEP groups, and 3 were significantly different, including fewer patients with hypoxemia (5.0% in the high level of PEEP group vs 13.6% in the low level of PEEP group; difference, −8.6% [95% CI, −11.1% to 6.1%]; P < .001). CONCLUSIONS AND RELEVANCE Among obese patients undergoing surgery under general anesthesia, an intraoperative mechanical ventilation strategy with a higher level of PEEP and alveolar recruitment maneuvers, compared with a strategy with a lower level of PEEP, did not reduce postoperative pulmonary complications.

Although recent work has suggested that lymphopenia-induced homeostatic proliferation may improve T cell-mediated tumor rejection, there is little direct evidence isolating homeostatic proliferation as an experimental variable, and the mechanism by which improved antitumor immunity occurs via homeostatic proliferation is poorly understood. An adoptive transfer model was developed in which tumor-specific 2C/RAG2−/− TCR transgenic CD8+ T cells were introduced either into the lymphopenic environment of RAG2−/− mice or into P14/RAG2−/− mice containing an irrelevant CD8+ TCR transgenic population. RAG2−/−, but not P14/RAG2−/− recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection. Despite absence of tumor rejection in P14/RAG2−/− recipients, 2C cells did become activated, as reflected by CFSE dilution and CD44 up-regulation. However, these cells showed poor IFN-γ and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag. To determine whether homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG−/− recipients, which resulted in vigorous homeostatic proliferation, recovery of IL-2 production, and acquisition of the ability to reject tumors. Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or re-establishing T cell responsiveness.

Experimental evidence suggests that a type 1 T cell response may result in optimal tumor rejection in vivo. This phenotype is determined in part by cytokines that influence T cell differentiation. In transplantable tumor models such as P1.HTR, tumors grow progressively despite expression of defined tumor Ags. We hypothesized that this failure to reject may be due to poor generation of a type 1 phenotype, through a dominant influence of the type 2-promoting cytokines IL-4 and/or IL-13. This hypothesis was tested by implanting P1.HTR tumors into mice deficient in Stat6. In contrast to progressive growth of P1.HTR tumors in wild-type mice, and aggressive growth even of IL-12-transfected P1.HTR in Stat1−/− mice, P1.HTR was spontaneously rejected by Stat6−/− mice. Rejection was accompanied by augmented tumor-specific IFN-γ production and CTL activity. These results suggest that pharmacologic inhibition of Stat6 signaling could potentiate anti-tumor immunity in vivo.