Anna Johansson

Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy

Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFNγ and/or TNFα into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNγ causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNFα enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8+ effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNFα stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNFα substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFα promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.

Protein contents in biological membranes can explain abnormal solvation of charged and polar residues.

Transmembrane helices are generally believed to insert into membranes based on their hydrophobicity. Nevertheless, there are important exceptions where polar residues have great functional importance, for instance the S4 helix of voltage-gated ion channels. It has been shown experimentally that insertion can be accomplished by hydrophobic counterbalance, predicting an arginine insertion cost of only 2.5 kcal/mol, compared with 14.9 kcal/mol in cyclohexane. Previous simulations of pure bilayers have produced values close to the pure hydrocarbon, which has lead to spirited discussion about the experimental conditions. Here, we have performed computer simulations of models better mimicking biological membranes by explicitly including protein helices at mass fractions from 15% to 55%, as well as an actual translocon. This has a striking effect on the solvation free energy of arginine. With some polar residues present, the solvation cost comes close to experimental observation at approximately 30% mass fraction, and negligible at 40%. In the presence of a translocon in the membrane, the cost of inserting arginine next to the lateral gate can be as low as 3–5 kcal/mol. The effect is mainly due to the extra helices making it easier to retain hydration water. These results offer a possible explanation for the discrepancy between the in vivo hydrophobicity scale and computer simulations and highlight the importance of the high protein contents in membranes. Although many membrane proteins are stable in pure bilayers, such simplified models might not be sufficiently accurate for insertion of polar or charged residues in biological membranes.

More than a scaffold: Stromal modulation of tumor immunity.

Current clinical success with anti-cancer immunotherapy provides exciting new treatment opportunities. While encouraging, more needs to be done to induce durable effects in a higher proportion of patients. Increasing anti-tumor effector T cell quantity or quality alone does not necessarily correlate with therapeutic outcome. Instead, the tumor microenvironment is a critical determinant of anti-cancer responsiveness to immunotherapy and can confer profound resistance. Yet, the tumor-promoting environment - due to its enormous plasticity - also delivers the best opportunities for adjuvant therapy aiming at recruiting, priming and sustaining anti-tumor cytotoxicity. While the tumor environment as an entity is increasingly well understood, current interventions are still broad and often systemic. In contrast, tumors grow in a highly compartmentalized environment which includes the vascular/perivascular niche, extracellular matrix components and in some tumors lymph node aggregates; all of these structures harbor and instruct subsets of immune cells. Targeting and re-programming specific compartments may provide better opportunities for adjuvant immunotherapy.

Risk of Renal Cell Carcinoma After Hysterectomy

BACKGROUND Hysterectomy is the most common gynecologic operation among women; study findings indicate that hysterectomy is associated with renal cell carcinoma. METHODS To assess the effects of hysterectomy on the incidence and risk of renal cell carcinoma, we performed a population-based cohort study using data from 184,945 women who had undergone hysterectomy (hereafter referred to as women with hysterectomy) and from 657,288 matched women who had not undergone hysterectomy (hereafter referred to as women without hysterectomy) by linking nationwide Swedish health care registers, including the Swedish Inpatient Register and the Swedish Cancer Register (January 1, 1973, through December 31, 2003). Risk of renal cell carcinoma owing to hysterectomy status was assessed using Cox proportional hazards regression models with hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS The crude incidence rates of renal cell carcinoma were 17.4 cases per 100,000 person-years among women with hysterectomy and 13.1 cases per 100,000 person-years among women without hysterectomy. This corresponded to an adjusted overall HR of 1.50 (95% CI, 1.33-1.69) for renal cell carcinoma among women with hysterectomy vs women without hysterectomy. The risk of renal cell carcinoma was age dependent, and the highest risk was found within 10 years of surgery among women who underwent hysterectomy at age 44 years or younger (HR, 2.36; 95% CI, 1.49-3.75). The overall risk of renal cell carcinoma after hysterectomy was consistently increased and of similar magnitude over the time strata: HR, 1.50 (95% CI, 1.26-1.78) for years 0 to 10; 1.49 (1.22-1.82) for years 11 to 20; and 1.51 (1.05-2.16) for more than 20 years after surgery. CONCLUSIONS Hysterectomy for benign indications was significantly associated with renal cell carcinoma. Women undergoing the procedure at a young age were at particular risk.

Remodeling of Tumor Stroma and Response to Therapy

Solid tumors are intrinsically resistant to therapy. Cancer progression occurs when tumor cells orchestrate responses from diverse stromal cell types such as blood vessels and their support cells, inflammatory cells, and fibroblasts; these cells collectively form the tumor microenvironment and provide direct support for tumor growth, but also evasion from cytotoxic, immune and radiation therapies. An indirect result of abnormal and leaky blood vessels in solid tumors is high interstitial fluid pressure, which reduces drug penetration, but also creates a hypoxic environment that further augments tumor cell growth and metastatic spread. Importantly however, studies during the last decade have shown that the tumor stroma, including the vasculature, can be modulated, or re-educated, to allow better delivery of chemotherapeutic drugs or enhance the efficiency of active immune therapy. Such remodeling of the tumor stroma using genetic, pharmacological and other therapeutic approaches not only enhances selective access into tumors but also reduces toxic side effects. This review focuses on recent novel concepts to modulate tumor stroma and thus locally increase therapeutic efficacy.

Intratumoral TNFα improves immunotherapy

Solid tumors are frequently resistant to immunotherapy. We demonstrated that low-dose tumor necrosis factorα (TNFα), when directly targeted to the tumor environment, exerts dual effects by improving vessel functionality and activating immune cells. This vascular remodeling in an inflammatory context enhances active immunotherapy and promotes tumor regression.