Purpose: Cancer associated fibroblasts (CAFs) are an important component of the tumor microenvironment (TME), but a systematic investigation of their molecular characteristics and clinical relevance are lacking. Here, we sought to compare CAFs across multiple cancer types to identify critical molecular pathways activated in CAF subtypes, which may contribute to clinical outcome, disease progression, and immunotherapy resistance. Experimental Design:We performed integrated analysis of CAFs from melanoma (MEL), head and neck squamous cell carcinoma (HNSC), and lung cancer (LC), and identified the molecular characteristics that are distinctly active in each CAF subtype. Gene signatures for individual CAF subtypes were identified and used to study the association of subtype abundance with clinical outcome and immunotherapy resistance. Results:We identified six CAF subtypes (pan-CAFs) shared across cancer types and uncovered the molecular characteristics and genetic pathways distinguishing them. Interestingly, these CAF subtypes express distinct immunosuppressive factors, such as CXCL12 and CXLC14, and stemcell promoting factor IL-6. Additionally, we identified novel transcriptional drivers (MEF2C, TWIST1, NR1H3, RELB, and FOXM1) key to CAF heterogeneity. Furthermore, we showed that CAF subtypes were associated with different clinical outcomes and uncovered key molecular pathways that could activate or suppress cancer progression or were involved in resistance to anti-PD1 or anti-PD-L1 immunotherapy.

Pre-exposure prophylaxis (PrEP) uptake has been extremely low among key groups. PrEP-related stigma and shaming are potential barriers to uptake and retention in PrEP programs. There is a lack of literature describing PrEP stigma. In order to fill this gap, we recruited online 43 HIV-negative Men who have Sex with Men (MSM) who use PrEP. Semistructured interviews were conducted to explore their perceptions and experience of stigma related to PrEP use. Data were analyzed using Strauss and Corbin’s grounded theory and constant comparison techniques to enhance understanding of the lived experiences of MSM who use PrEP. The participants experienced PrEP stigma as rejection by potential/actual partners, stereotypes of promiscuity or chemsex, and labeling of both the user and the medication. They connected PrEP stigma with HIV stigma, generational differences, moralization of condom use, and inability to embrace one’s own sexuality. These findings point to a need to develop tailored interventions to address PrEP-related stigma and shaming for individuals, health-care professionals, and the MSM community-at-large.

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The B7 family ligand HERV-H LTR–associating protein 2 (HHLA2) is an attractive target for cancer immunotherapy because of its coinhibitory function, overexpression in human cancers, and association with poor prognoses. However, the knowledge of the HHLA2 pathway is incomplete. HHLA2 has an established positive receptor transmembrane and immunoglobulin (Ig) domain containing 2 (TMIGD2) but a poorly characterized negative receptor human killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3). Here, KIR3DL3 and TMIGD2 simultaneously bound to different sites of HHLA2. KIR3DL3 was mainly expressed on CD56dim NK and terminally differentiated effector memory CD8+ T (CD8+ TEMRA) cells. KIR3DL3+ CD8+ TEMRA acquired an NK-like phenotype and function. HHLA2 engagement recruited KIR3DL3 to the immunological synapse and coinhibited CD8+ T and NK cell function and killing, inducing immune-evasive HHLA2+ tumors. KIR3DL3 recruited SHP-1 and SHP-2 to attenuate Vav1, ERK1/2, AKT, and NF-κB signaling. HHLA2+ tumors from human kidney, lung, gallbladder, and stomach were infiltrated by KIR3DL3+ immune cells. KIR3DL3 blockade inhibited tumor growth in multiple humanized mouse models. Thus, our findings elucidated the molecular and cellular basis for the inhibitory function of KIR3DL3, demonstrating that the KIR3DL3-HHLA2 pathway is a potential immunotherapeutic target for cancer.

Purpose Current clinical parameters do not stratify indolent from aggressive prostate cancer (PCa). Aggressive PCa, defined by the progression from localized disease to metastasis, is responsible for the majority of PCa-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of PCa patients, however they have yet to provide targeted therapy approaches that could inhibit a patient’s progression to metastatic disease. Experimental Design We have interrogated a total of seven primary PCa cohorts (N = 1,900), two metastatic castration resistant PCa datasets (N = 293) and one prospective cohort (N = 1,385) to assess the impact of TOP2A and EZH2 expression on PCa cellular program and patient outcomes. We also performed immunohistochemical staining for TOP2A and EZH2 in a cohort of primary PCa patients (N = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel PCa-derived murine cell lines. Results We demonstrate by genome-wide analysis of independent primary and metastatic PCa datasets that concurrent TOP2A and EZH2 mRNA and protein up-regulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in PCa cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions Overall, our data supports further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neo-adjuvant targeted therapy approaches.