Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.

Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade. Immunity 2016 Apr 19; 44(4):924-38

Expansion and Activation of CD103 + Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition

CILJ: iz dijela istraživanja komorbiditeta pušača u riziku nastanka KOPB-a u sklopu projekta MARKO utvrditi postoje li razlike između spolova u odnosu na stanovanje u urbanoj ili ruralnoj sredini te u odnosu na pušački staž prema GOLD klasifikaciji bolesti kod pušača. Naknadni cilj je bio utvrditi epidemiološke osobitosti kroničnih bolesti donjeg dišnog sustav (KBDDS) u Splitsko-dalmatinskoj županiji (SDŽ) u odnosu na Republiku Hrvatsku (RH). MATERIJAL I METODE: prvi istraživački dio završnog rada urađen je u vidu presječne studije po načelima projekta MARKO provedenog 2010.-2011. godine kod 124 izabrana ispitanika pušača dobi 20-64 godine bez prethodno utvrđene KOPB-i i drugih stanja koja bitno odudaraju od zdravog dijela populacije. Epidemiološke osobitosti Splitsko-dalmatinske županije je retrospektivna studije pobola i smrtnosti od KBDDS. U oba dijela završnog rada korišten je komparativni epidemiološki metod. Standardizacija stopa pobola i smrtnosti urađena je direktnom metodom prema Europskoj standardnoj populaciji 2013 (ESP 2013). Statistička značajnost izračunata je χ²-testom, Studentovim t-testom, stope su prikazane uz 95% CI (Confidence Interval), značajnost razlika na razini pouzdanosti P<0,05 ili većoj. REZULTATI: unatoč činjenici da je uzorak od 124 ispitanika sadašnjih i bivših pušača visoko probran od strane njihovih liječnika obiteljske medicine i da je to mali nereprezentativan uzorak bez punovrijedne kontrolne skupine moglo se utvrditi da po GOLD klasifikaciji nema značajnosti razlika između muškog i ženskog spola niti između urbanog i ruralnog područja za sve ispitanike. Međutim u raščlambi ispitanika podijeljenih obzirom na duljinu pušačkog staža do i preko 40 godina kod muškog spola te do 30 i preko 30 godina kod ženskog spola utvrđene su statistički značajne razlike. Kod ispitanika Grada Splita s većim pušačkim stažom uopće nema zdravih pušača kod oba spola dok je i simptomatskih pušača statistički značajno više (P<0,01). Po zastupljenosti komorbiditeta koji je zabilježen kod 73 ispitanika za devet utvrđenih bolesti/stanja prednjače hipertenzija i hiperlipidemija. Statistički značajno veći udio (%) ispitanika bez bolesti tzv. „zdravi pušači“ utvrđen je kod ruralnog stanovništva u općinama 66,7% vs. 31,0% (χ²-test=6,52; P<0,05). Ispitanici oba spola Grada Splita imali su statistički značajno veći udio zbira svih komorbiditeta nego stanovnici općina 92,9% vs. 66,7% (χ²-test=14,26; P<0,001) kao i statistički značajno veći udjel ispitanika s jednom bolešću (45,2%) u odnosu na ispitanike iz općina (8,3%) (χ²-test=7,96; P<0,01). Ovakva razlika posljedica je većih udjela kod muškog spola dok kod ženskog spola nema značajnosti razlika. U odnosu na ukupno stanovništvo SDŽ dobi 20-64 godine kod ispitanika pušača u riziku na nastanak KOPB-a statistički je značajno veći pobol od hipertenzije i peptičkog sindroma. Statstički je značajno manji pobol od afektivnih poremećaja dok kod dijabetes melitusa, miokardiopatije, bolesti štitanjače i reumatskih bolesti nema značajnosti razlika. Rezultati istraživanja sukladni su spoznajama iz epidemioloških razmatranja. Prosječna godišnja smrtnost od KBDDS u SDŽ u razdoblju 2007.-2015. godine 22,21/100.000 za oba spola statistički je značajno niža od prosječne godišnje smrtnosti za RH 37,50/100.000, a poglavito od prosječne godišnje smrtnosti stanovnika kontinentalnih županija RH 41,77/100.000. ZAKLJUČAK: Iz rezultata istraživanja, premda bez rezultata druge faze istraživanja, kao i rezultata epidemiološke raščlambe smrtnosti od KBDDS u SDŽ može se nedvojbeno i nepobitno zaključiti da je pušenje duhana predominantni uzrok pobola i smrtnosti od KBDDS a time i same KOPB-i. Unatoč dobrim rezultatima u RH i još boljim u SDŽ mnogo više se može postići radom na primarnoj prevenciji KBDDS, a to je stalna borba protiv duhanskog dima. Svi zdravstveni djelatnici moraju u tome sudjelovati i u narednim godinama što skorije doprinijeti smanjenju udjela pušača s jedne trećine na jednu četvrtinu ukupnog stanovništva. Posebno mjesto u tim nastojanjima pripada medicinskim sestrama prvostupnicama educiranima i pripremljenima za rad u zajednici na težišnoj zadaći primarnoj prevenciji KBDDS i raka pluća.AIM: The aim of the research is to determine according to the GOLD Classification of Smokers' Disease whether there are differences between the sexes in smoking time and it’s relation to housing in the urban or rural environment. This was the personal part of the research of the smoking co-morbidity and the risk of chronic obstructive pulmonary disease (COPD) development within the MARKO project. The ultimate goal was to establish the epidemiological characteristics of chronic diseases of the lower respiratory system (CDLRS) in the Split-Dalmatia County (SDC) in relation to the Republic of Croatia. MATERIAL AND METHODS: The personal research part of the final work was carried out in the form of a cross-sectional study on the principles of the MARKO project implemented in 2010-2011. There was 124 selected smokers aged 20-64, without previously established COPD and other conditions that significantly deviate from the healthy part of the population. The epidemiological features of the SDC are retrospective studies of mortality by CDLRS. In both parts of the final work a comparative epidemiological method was used. The standardization of mortality and mortality rates was done by a direct method according to the European Standard Population 2013 (ESP 2013). Statistical significance was calculated by the χ²-test, Student's t-test, with 95% CI (Confidence Interval), the significance of differences on the level of reliability P <0.05 or greater. THE RESULTS: Despite the fact that a sample of 124 current and ex-smokers tested by their family medicine practitioners and that this small, non-representative sample without a full-time control group it could be established according to GOLD classification that there is no significant difference between male and female gender or between urban and rural area for all respondents. However, in the analysis of the respondents divided by the length of smoking time up to and over 40 years in male sex and up to 30 and over 30 years in the female sex, statistically significant differences were found. There are no healthy smokers in both sexes at the time of the questioning of the City of Split with a higher smoking age, while the symptomatic smokers are statistically significantly higher (P <0.01). By the presence of comorbidity observed in 73 subjects for nine predetermined disease /states, hypertension and hyperlipidemia are leading ones. Statistically significantly higher proportion (%) of patients with no illness so called "Healthy smokers" were found in the rural population in the municipalities of 66.7% vs. 31.0% (χ²-test = 6.52, P <0.05). The subjects of both sexes of the City of Split had a statistically significantly higher proportion of all comorbidity than the inhabitants of the municipalities 92.9% vs. 66.7% (χ²-test = 14.26; P <0.001) as well as statistically significantly higher proportion of subjects with single disease (45.2%) compared to district respondents (8.3%) (χ²-test = 7.96; P <0.01). This difference is the result of higher share in male sex, while in the female gender there is no significant difference. Compared to the total population of the population aged 20-64 years in the smokers' risk of developing COPD, there is a statistically significant increase in the prevalence of hypertension and peptic syndrome. There is a statistically significant decrease in affective disorders, while there is no significant difference in diabetes mellitus, myocarditis, shingles and rheumatic diseases. The results of personal research are consistent with epidemiological considerations. Average annual mortality from CDLRS in SDC in the period 2007-2015 year 22.21 / 100.000 for both sexes is statistically significantly lower than the average annual mortality rate for Croatia 37.50 / 100.000, and especially from the average annual mortality rate of the continental counties of Croatia 41.77 / 100.000. CONCLUSION: From the results of the personal research, although without the results of the second phase of the research and the results of the epidemiological analysis of the mortality of CDLRS in the SDC, it can be conclusively and irrefutably state that tobacco smoking is the predominant cause of the disease and mortality of CDLRS and COPD itself. Despite the good results in the Republic of Croatia and even better in the SDC, much more can be achieved by working on primary prevention of CDLRS, which is a constant fight against tobacco smoke. All health professionals must participate in the coming years as soon as possible to reduce the share of smokers from one third to one quarter of the total population. A special place in these endeavors belongs to nurses who are educated and prepared for work in the community on the primary task of primary prevention of CDLRS and lung cancer