Summary Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8 + T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4 + T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4 + T cell states that are clonally expanded. These CD4 + T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4 + T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.

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IMPORTANCE Biased patient behavior negatively impacts resident well-being. Data on the prevalence and frequency of these encounters are lacking and are needed to guide the creation of institutional trainings and policies to support trainees. OBJECTIVE To evaluate the frequency of resident experiences with and responses to a range of biased patient behaviors. DESIGN, SETTING, AND PARTICIPANTS A retrospective survey was sent via email to 331 secondand third-year internal medicine residents from 3 academic medical centers in California and North Carolina. First-year residents were excluded owing to their limited interactions with patients at the time of participant recruitment. Data were collected from August 21 to November 25, 2019. MAIN OUTCOMES AND MEASURES Descriptive statistics were used to report the frequency of experience of various types of biased patient behavior, residents' responses, the factors impeding residents' responses, and residents' experiences and beliefs regarding training and policies. RESULTS Overall, 232 of 331 residents (70%) participated; 116 (50%) were women; 116 of 247 (47%) were White (participants had the option of selecting >1 race/ethnicity); and 23 (10%) identified as lesbian, gay, bisexual, transgender, or queer. The frequency of resident-reported experience of types of biased patient behaviors varied. The most common behaviors-belittling comments and assumption of nonphysician status-were reported to be experienced 1 or more times per week by 14% of residents (32 of 231) and 17% of residents (38 of 230), respectively. Women, Black or Latinx, and Asian residents reported experiencing biased behavior more frequently. Forty-five percent of Black or Latinx residents (17 of 38) encountered instances of explicit epithets or rejection of care. All 70 Asian residents reported experiencing inquiries into their ethnic origins. Most women residents (110 of 115 [96%]) experienced role questioning behaviors, and 87% (100 of 115) experienced sexual harassment. The need to prioritize clinical care and a sense of futility in responding were the most common factors (cited by 34% of residents [76 of 227] and 25% of residents [56 of 227], respectively) significantly impeding responses to biased behaviors. Eighty-five percent of residents (191 of 226) never reported incidents to their institution. Eighty-nine percent of residents (206 of 232) identified training and policies as necessary or very necessary. CONCLUSIONS AND RELEVANCE This survey study suggests that biased patient behavior is experienced frequently by internal medicine residents. Non-White and women residents reported experiencing a disproportionate burden of these incidents. Residents' responses rarely included institutional involvement. Residency programs and health care systems should prioritize training and policies to address biased patient behavior and support affected residents.

Background COVID-19 vaccination rates are lower among historically marginalized populations, including Black/African American and Latinx populations, threatening to contribute to already high COVID-19 morbidity and mortality disparities for these groups. We conducted a community-based participatory research study using qualitative methods to explore knowledge and beliefs about COVID-19 vaccination among Black/African American, Latinx, and Chinese American residents of the San Francisco Bay Area and assess their views on vaccination outreach and delivery strategies. Methods and findings Data were collected from January 14, 2021, to February 24, 2021, with adult residents (N = 109 [Female: N = 76; 70%]) in San Francisco. Focus groups (N = 10) and in-depth interviews (N = 25) were conducted among Black/African Americans (N = 35), Latinx (N = 40), and Chinese Americans (n = 34) in English, Spanish, Cantonese, or Mandarin. Themes were identified using grounded field theory, and included misinformation, mistrust of government and health institutions, and linguistic and other barriers to vaccine access. All three racial/ethnic groups had experiences with vaccine misinformation and information overload. Many African American and Latinx participants cited structural and interpersonal racism, and anti-immigrant discrimination, as factors reducing their trust in government and public health disseminated information and their willingness to be vaccinated. Participants expressed trust in community-based organizations, including faith-based organizations and community-run clinics. Participants often experienced barriers to vaccine access, such as transportation to drive-in sites, with Latinx and Chinese American groups also frequently citing language barriers. Conclusions Vaccine outreach strategies must acknowledge how longstanding systemic, institutional, and structural racism contributes to mistrust in government and health institutions and engage with and support trusted messengers from the community to eliminate cultural, linguistic, and other barriers to vaccine access.