CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy.

Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a vaccine (PancVAX2) targeting both major histocompatibility complex class I- (MHCI-) and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T cells into the tumor with lower PD-1 expression after reactivation compared with the CD8+ vaccine alone. Vaccine-induced neoantigen-specific Th1 CD4+ T cells in the tumor were associated with decreased Tregs. Consistent with this, PancVAX2 was associated with more proimmune myeloid-derived suppressor cells and M1-like macrophages in the tumor, demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4+ T cell-specific neoantigens for personalized cancer vaccine modalities.

The Relationship Between Posttraumatic Stress Disorder and Alcohol Misuse and Smoking Among Aging Men Who Have Sex With Men: No Evidence of Exercise or Volunteering Impact.

OBJECTIVES: To determine if the association between posttraumatic stress disorder (PTSD) and substance use (alcohol misuse or smoking tobacco) is mediated/moderated by exercise or volunteering among aging (≥40 years) men who have sex with men (MSM), and if this mediation/moderation differs by HIV serostatus. METHODS: Multicenter AIDS Cohort Study data were used. Three datasets with PTSD measured during different time periods (10/1/2017-3/31/2018, 898 men; 4/1/2018-9/30/2018, 890 men; 10/1/2018-3/31/2019, 895 men) were analyzed. Longitudinal mediation analyses estimated the mediation effect of exercise and volunteering on the outcomes. RESULTS: Nine percent of MSM had evidence of PTSD. There was no statistically significant mediation effect of exercise or volunteering regardless of substance use outcome. The odds of smoking at a future visit among MSM with PTSD were approximately double those of MSM without PTSD. Results did not differ by HIV serostatus. DISCUSSION: There is a particular need for effective smoking cessation interventions for aging MSM with PTSD.

Comparison of anal pre-cancer screening strategies among men who have sex with men.

PURPOSE: Comparison of anal pre-cancer screening strategies in men who have sex with men (MSM). METHODS: MSM in the Multicenter AIDS Cohort Study underwent repeated anal cytology (aCyt), oncogenic human papillomavirus (oncHPV) testing. A subset received High-Resolution Anoscopy (HRA). We evaluated three screening strategies for their ability to predict anal histological High-Grade Squamous Intraepithelial lesion (HSIL): single aCyt, sequential aCyt, and oncHPV co-testing. Multivariable logistic regression models evaluated risk of HSIL among participants undergoing HRA within 5 years of screening. Sensitivity and specificity were estimated among participants with HRA, and results corrected for verification bias using weighted generalized estimating equations. RESULTS: There were 1426 MSM with aCyt screening (48% people with HIV [PWH]) and 428 that underwent HRA. Median age was 57 years, 14% of PWH had CD4< 350 cells/mm3. HSIL probability was higher in MSM with one (39%, p < 0.01) or two abnormal aCyt results (46%, p < 0.01), versus those with normal aCyt (23-24%). Among men with abnormal aCyt, men with oncHPV+ had significantly higher risk than those who were oncHPV- (47% vs. 16%, p < 0.01). Specificity was modest with single aCyt+ (50%) but increased with sequential aCyt+ (79%) or oncHPV+ (67%). Sensitivity was high with single oncHPV+ (88%), moderate with single aCyt+ (66%) and oncHPV+ co-testing (61%), and low with sequential aCyt+ (39%). After correcting for potential verification bias, specificity increased and sensitivity decreased, but inferences were similar. CONCLUSION: None of the screening strategies evaluated had both sufficient specificity and sensitivity to warrant routine widespread use.

Trans women have worse cardiovascular biomarker profiles than cisgender men independent of hormone use and HIV serostatus.

BACKGROUND: Feminizing hormonal therapy (FHT) and HIV potentially alter cardiovascular disease (CVD) risk in transgender women (TW). METHODS: TW were enrolled in Los Angeles, California and Houston, Texas and frequency-matched to Multicenter AIDS Cohort Study cisgender men (CM) on age, race, substance use, and abacavir use. Biomarkers of CVD risk and inflammation were assessed via ELISA. Wilcoxon rank sum and Fisher's exact tests compared TW and CM. Multivariable linear regression assessed factors associated with biomarker concentrations. RESULTS: TW (HIV+ n  = 75, HIV- n  = 47) and CM (HIV+ n  = 40, HIV- n  = 40) had mean age 43-45 years; TW/CM were 90%/91% non-Hispanic Black, Hispanic, or Multiracial, 26%/53% obese, and 34%/24% current smokers; 67% of TW were on FHT. Among people with HIV (PWH), TW had higher median extracellular newly-identified receptor for advanced glycation end-products (EN-RAGE), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), soluble tumor necrosis factor receptor type (sTNFR) I/II, interleukin (IL)-8 and plasminogen activator inhibitor (PAI)-1, but lower soluble CD14, von Willebrand factor (vWF) and endothelin (ET)-1 levels than CM. Findings were similar for participants without HIV (all P  < 0.05). In multivariable analysis, TW had higher EN-RAGE, IL-6, IL-8, P selectin, PAI-1, oxLDL and sTNFRI/II concentrations, and lower vWF, independent of HIV serostatus and current FHT use. Both being a TW and a PWH were associated with lower ET-1. CONCLUSIONS: Compared to matched cisgender men, trans women have altered profiles of biomarkers associated with systemic inflammation and CVD. Further work is needed to decipher the contributions of FHT to CVD risk in TW with HIV.

Risk of smoking-related cancers among women and men living with and without HIV.

OBJECTIVES: We investigated whether the effect of smoking on the incidence of smoking-related cancers differs by HIV-infection status, if sex modifies the impact of risk factors for smoking-related cancers, and the sex-specific attributable risk of smoking on cancer incidence. DESIGN: Data from two large prospective studies in the United States were analyzed: 6789 men in the Multicenter AIDS Cohort Study from 1984 through 2018 and 4423 women in the Women's Interagency HIV Study from 1994 through 2018. METHODS: Incidence rates, relative risks, and adjusted population attributable fractions (PAFs) were calculated for smoking-related cancers. RESULTS: During study follow-up, there were 214 incident smoking-related cancers in the men and 192 in the women. The age-adjusted incidence ratess for smoking-related cancers were higher in the women (392/100 000) than for the men (198/100 000; P < 0.01) and higher for people living with HIV (PLWH, 348/100 000) than for those without HIV (162/100 000; P < 0.01). Unadjusted incidence rates in PLWH were higher than in those without HIV when stratifying by cumulative pack-years of smoking (all P values <0.01). In adjusted interaction models, the effects of cumulative pack-years of smoking were significantly stronger in women. The adjusted PAFs for smoking-related cancers were nonsignificantly higher in the women than in the men (39 vs. 28%; P = 0.35). CONCLUSION: HIV looks to be an independent risk factor for smoking-related cancers and women appear to have a greater risk than men. These results highlight the need for interventions to help PLWH, especially women, quit smoking and sustain cessation to reduce their risk of smoking-related cancers.

Understanding Geospatial Factors Associated With Cervical Cancer Screening Uptake in Amazonian Peruvian Women.

PURPOSE: Cervical cancer (CC) is the most common and second-most deadly cancer among Peruvian women. Access to services is strongly associated with CC screening uptake. This study investigated geospatial features contributing to utilization of screening. We used geolocated data and screening information from a Knowledge, Attitudes, and Practice (KAP) survey implemented in Iquitos, Peru in 2017. MATERIALS AND METHODS: The KAP collected cross-sectional CC screening history from 619 female interviewees age 18-65 years within 5 communities of varying urbanization levels. We used spatial statistics to determine if screened households tended to cluster together or cluster around facilities offering screening in greater numbers than expected, given the underlying population density. RESULTS: On the basis of K-functions, screened households displayed greater clustering among each other as compared with clustering among unscreened households. Neighborhood-level factors, such as outreach, communication, or socioeconomic condition, may be functioning to generate pockets of screened households. Cross K-functions showed that screened households are generally located closer to health facilities than unscreened households. The significance of facility access is apparent and demonstrates that travel and time barriers to seeking health services must be addressed. CONCLUSION: This study highlights the importance of considering geospatial features when determining factors associated with CC screening uptake. Given the observed clustering of screened households, neighborhood-level dynamics should be further studied to understand how they may be influencing screening rates. In addition, results demonstrate that accessibility issues must be carefully considered when designing an effective cancer screening program that includes screening, follow-up, and treatment.