Designing meaningful continuous representations of T cell receptor sequences with deep generative models.

T Cell Receptor (TCR) antigen binding underlies a key mechanism of the adaptive immune response yet the vast diversity of TCRs and the complexity of protein interactions limits our ability to build useful low dimensional representations of TCRs. To address the current limitations in TCR analysis we develop a capacity-controlled disentangling variational autoencoder trained using a dataset of approximately 100 million TCR sequences, that we name TCR-VALID. We design TCR-VALID such that the model representations are low-dimensional, continuous, disentangled, and sufficiently informative to provide high-quality TCR sequence de novo generation. We thoroughly quantify these properties of the representations, providing a framework for future protein representation learning in low dimensions. The continuity of TCR-VALID representations allows fast and accurate TCR clustering and is benchmarked against other state-of-the-art TCR clustering tools and pre-trained language models.

Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

BACKGROUND: Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab. METHODS: Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing. RESULTS: Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here. CONCLUSIONS: This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.

Stress and coping amongst cisgender male partners of transgender women.

The cisgender male partners of transgender women have received little attention beyond their sexual behaviour. This is an issue, as marginalisation and social environments determine sexual behaviour and subsequent health outcomes. This article assesses in-depth interviews with cisgender male partners of transgender women in Atlanta and Baltimore, USA. Analysis suggests men experience minority stress that may lead to ameliorative coping processes such as coming out and LGBTQ group affiliation. Specifically, the interviews identify stressful, marginalising reactions from family and friends concerning men's relationships with transgender women. In turn, men described uniquely supportive ties to LGBTQ communities, which included ongoing relationships with transgender women, having close sexual and gender minority friends, and occupying notably LGBTQ spaces such as Pride events. The LGBTQ social connectivity of the cisgender male partners of transgender women could prove critical to future targeted HIV prevention efforts.

Uncaring landscapes and HIV peer support in the rural Southern United States.

Despite social determinants being central to LGBTQ health inequities, they are scarcely targeted by federal public health interventions. Racism, sexual stigma, and social disconnection, in particular, contribute to numerous LGBTQ health inequities including HIV. This article explores the case of a peer support group at a federally supported HIV care center in a rural Southern (US) location alongside oral history interviews with queer-identifying Black men recorded in the same region. Geographies of care literature center trusting social relations in care provision. For the narrators, unchecked harmful social relations vis a vis stigma and disconnection from queer collectivity produce an 'uncaring landscape' in the geographic environment. The peer support group diverged from the stipulated context of HIV to offer space for queer collectivity and destigmatizing social care. The findings support a more radical, expansive provision of state-supported care for sexual minorities.

"In the Bible Belt:" The role of religion in HIV care and prevention for transgender people in the United States South.

Within the United States South, the socio-religious norms that shape life for many residents may have public health implications. Drawing from 12 key informant interviews, this study explores the role of religious institutions in HIV care and prevention access among transgender people of color in Southern cities. Findings suggest that while religious anti-transgender stigma is pervasive, the regional importance of faith-based beliefs and institutions necessitates targeted faith-based initiatives for the population. Broadly, findings suggest regional environments may demand interventions that negotiate historically marginalizing relationships between at-risk groups and dominant cultural institutions.

Stigma in place: Black gay men's experiences of the rural South.

Black gay men (MSM) in the rural United States South are inequitably burdened by stigmatization and the HIV epidemic. Drawing from twelve oral history interviews with middle-aged and older Black gay narrators from rural North Carolina, this research explores the impact of sexual marginalization and the HIV epidemic on lived experiences of the rural South. Despite describing increasingly empowered views of HIV and sexual health, narrators expressed persistent difficulty managing social determinants of HIV vulnerability-sexual stigma and disconnection from LGBTQ collectivity. Narrators reported better managing sexual marginalization over their lifetimes in urban settings and places outside of the South such as New York (NY). This research suggests stressful structural and interpersonal experiences of stigma may define lived experiences of particular settings.