ABSTRACT
Genomic profiling has identified several molecular oncodrivers in breast tumorigenesis. A thorough understanding of endogenous immune responses to these oncodrivers may provide insights into immune interventions for breast cancer (BC). We investigated systemic anti-HER2/neu CD4+ T-helper type-1 (Th1) responses in HER2-driven breast tumorigenesis. A highly significant stepwise Th1 response loss extending from healthy donors (HD), through HER2pos-DCIS, and ultimately to early stage HER2pos-invasive BC patients was detected by IFNγ ELISPOT. The anti-HER2 Th1 deficit was not attributable to host-level T-cell anergy, loss of immune competence, or increase in immunosuppressive phenotypes (Treg/MDSCs), but rather associated with a functional shift in IFNγ:IL-10-producing phenotypes. HER2high, but not HER2low, BC cells expressing IFNγ/TNF-α receptors were susceptible to Th1 cytokine-mediated apoptosis in vitro, which could be significantly rescued by neutralizing IFNγ and TNF-α, suggesting that abrogation of HER2-specific Th1 may reflect a mechanism of immune evasion in HER2-driven tumorigenesis. While largely unaffected by cytotoxic or HER2-targeted (trastuzumab) therapies, depressed Th1 responses in HER2pos-BC patients were significantly restored following HER2-pulsed dendritic cell (DC) vaccinations, suggesting that this Th1 defect is not "fixed" and can be corrected by immunologic interventions. Importantly, preserved anti-HER2 Th1 responses were associated with pathologic complete response to neoadjuvant trastuzumab/chemotherapy, while depressed responses were observed in patients incurring locoregional/systemic recurrence following trastuzumab/chemotherapy. Monitoring anti-HER2 Th1 reactivity following HER2-directed therapies may identify vulnerable subgroups at risk of clinicopathologic failure. In such patients, combinations of existing HER2-targeted therapies with strategies to boost anti-HER2 CD4+ Th1 immunity may decrease the risk of recurrence and thus warrant further investigation.
ABSTRACT
OBJECTIVE: To perform a national climate survey of general surgery residents regarding attitudes and perceptions of the influence of sexual orientation on the training experience. METHODS: A cross-sectional voluntary online survey was distributed to all Accreditation Council for Graduate Medical Education-accredited general surgery programs. Residents self-identified as heterosexual, lesbian, gay, or bisexual. Descriptive statistics were performed. For the purposes of further analysis, respondents were classified as heterosexual or LGBT. Demographic characteristics and survey responses were examined by sexual orientation using the Fisher exact test. RESULTS: Of 388 resident respondents, 10 identified as lesbian (2.6%), 24 as gay (6.3%), and 9 as bisexual (2.4%). More than 30% of LGBT residents did not reveal their sexual orientation when applying for general surgery residency owing to fear of not being accepted. No statistical differences were found between LGBT and heterosexual residents regarding future career plans, happiness at work, good program fit, and rapport with fellow residents. Although no differences were found in relationship status between LGBT and heterosexual residents, more LGBT residents reported feeling uncomfortable openly discussing their spouse/partner with fellow residents (36% vs 3.0%, p < 0.001) and with surgical attending physicians (59% vs 9.3 %, p < 0.001) when compared with heterosexual peers. Additionally, LGBT residents felt more uncomfortable bringing their spouse/partner to formal surgery department events (42% vs 2.7%, p < 0.001). Among all respondents, 54% (n = 206) witnessed homophobic remarks by nurses and residents and 30% (n = 114) by surgical attending physicians. Of LGBT residents, 57% reported actively concealing their sexual orientation from fellow residents owing to fear of rejection and 52% from surgical attending physicians owing to fear of poor evaluations. LGBT residents reported experiencing targeted homophobic remarks by fellow residents (21%) and by surgical attending physicians (12%). None of the surgical residents who experienced directed homophobic remarks reported the event to their supervisors for reasons including fear of reprisal (13%-17%), not wanting to create more "trouble" (25%-50%), and a belief that nothing would be done about the event (17%-25%). CONCLUSION: Now, more than ever, issues related to sexual orientation have been at the forefront of political and public attention. No data exist that explore how these issues affect the training experience of general surgery residents. Our study showed that although there was no difference overall in reported work happiness or program fit, LGBT residents reported a greater need to conceal their personal lives from their surgery program peers and attending physicians. Whether these differences affect patient care, team work, career satisfaction, and personal cost of surgical training warrants further study.
