Hypothesis Proinflammatory cytokine Interleukin (IL)-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a pro-tumorigenic inflammatory phenotype, and inhibits anti-tumor immune responses. Experimental Design We generated bi-transgenic mice expressing a conditional IL-17A allele along with conditional KrasG12D and performed immune phenotyping of mouse lungs, survival analysis, and treatment studies with antibodies either blocking PD-1 or IL6, or depleting neutrophils. To support preclinical findings, we analyzed human gene expression datasets and immune profiled patient lung tumors. Results Tumors in IL-17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared to KrasG12D. IL-6, G-CSF, MFG-E8, and CXCL1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that tumor-associated neutrophils (TANs) were significantly elevated, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared to KrasG12D. In therapeutic studies PD-1 blockade was not effective in treating IL-17:KrasG12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T cell activation. In tumors from lung cancer patients with KRAS mutation we found a correlation among higher levels of IL-17A and the colony stimulating factor (CSF3), and a significant correlation among high neutrophil and lower T cell numbers. Conclusions Here we show that an increase in a single cytokine, IL-17A, without additional mutations, can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine/neutrophil depletion.

Background: Coccidioidomycosis or Valley Fever is caused by Coccidioides in Southwest US and Central America. Primary pulmonary infection is initiated by inhalation of air-borne arthroconidia. Since, lung is the first organ that encounters arthroconidia, different components of the pulmonary innate immune system may be involved in the regulation of host defense. Pulmonary surfactant proteins (SP)-A and SP-D have been recognized to play an important role in binding and phagocytosis of various microorganisms, but their roles in Coccidioides infection are not known.

Informed male volunteers completed maximal isometric knee extension efforts under each of three contraction conditions: 1) voluntary, 2) electrical stimulation (ES) only, and 3) superimposed (ES superimposed onto voluntary). Ten subjects completed the three contraction conditions using each of the following current formats: 1) asymmetrical biphasic rectangular wave, 2) asymmetrical biphasic spike wave, and 3) symmetrical monophasic square wave. Under the voluntary and the superimposed contraction conditions no significant differences in mean torque were observed between the three current formats. However, under the ES contraction condition, the torque associated with the symmetrical monophasic square wave was significantly less than that associated with the other two current formats. As well, the torque associated with the asymmetrical biphasic spike wave was significantly less than that associated with the asymmetrical biphasic rectangular wave format. No significant difference was observed between the maximum voluntary contraction (MVC) and the superimposed contraction conditions for the groups receiving the asymmetrical biphasic spike and the symmetrical monophasic square wave current formats, or between all three contraction conditions for the group receiving the asymmetrical biphasic rectangular wave format. However, the ES condition was associated with significantly less torque than were the MVC and the superimposed conditions for the asymmetrical biphasic spike and the symmetrical monophasic square wave formats. In response to a posttest questionnaire, 18 of 30 subjects felt that the ES contraction produced greater torque than did MVC, and 26 subjects selected the superimposed condition as having produced greater torque than the ES condition. The different current formats, resulting in different levels of sensation and preception, and the different output capabilities of each electrical stimulator are considered to have been jointly responsible for the ES only torque discrepancies. It is suggested that ES does not recruit more motor units, resulting in a greater force of contraction, than are recruited under MVC.J Orthop Sports Phys Ther 1984;5(6):324-331.

An acute bout of LF- and HF-NMES upregulated anabolic signaling with HF-NMES producing a greater anabolic response compared with LF-NMES, suggesting that HF stimulation may provide a stronger stimulus for processes that initiate muscle hypertrophy. In addition, the stimulation frequency parameter should be considered by clinicians in the design of optimal NMES treatment protocols.