Intratumoral CD8+ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer.

CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8+ TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8+ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. TRM-like CD8+ T cells could also provide local immune protection against tumor rechallenge and a TRM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.

Management of Late Relapses After Chemotherapy in Testicular Cancer: Optimal Outcomes with Dose-intense Salvage Chemotherapy and Surgery.

BACKGROUND: Late relapse (LR) in testicular cancer is defined as disease recurrence more than 2yr after primary treatment. Optimal management for this rare group is unknown. OBJECTIVE: To identify prognostic factors relevant to outcomes in a large LR series following primary treatment with platinum-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of all patients treated for advanced testicular cancer within the Anglian Germ Cell Cancer Network between 1995 and 2016. We identified 53 cases of LR following initial treatment for metastatic disease with platinum-based chemotherapy, and collected data on patient and tumour characteristics, treatments, and outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Progression-free survival (PFS) and overall survival (OS) were calculated for all patients. Survival curves were plotted according to the Kaplan-Meier method and univariate analysis of descriptive variables was performed using the log-rank method. RESULTS AND LIMITATIONS: Across the cohort, PFS at 36 mo was 41% and OS was 61%. Multiple factors were correlated with PFS. Use of dose-intense or high-dose chemotherapy was associated with better PFS compared to conventional-dose chemotherapy (PFS 48 vs 9.8 mo; p=0.0036). Resection of residual disease post-relapse chemotherapy was associated with better PFS (hazard ratio 3.46; p=0.0076). There was a nonsignificant trend towards worse PFS in very late (>7 yr) relapses. The study is limited by its retrospective nature and selection bias cannot be excluded. CONCLUSIONS: This study provides new insight into prognostic factors in LR. It confirms that surgery is critical to optimal outcomes, and suggests that dose-intense or high-dose chemotherapy in multisite nonresectable disease should be considered wherever feasible. PATIENT SUMMARY: We studied patients with testicular cancer that recurred at least 2yr after initial treatment with chemotherapy. We found that patients who are able to have surgery to remove cancer and who have more intensive chemotherapy may be more likely to live longer.

Dominance Hierarchies in Marine Invertebrates.

AbstractDominance hierarchies have been well studied in myriad terrestrial animals, but surprisingly little is known about hierarchies in marine invertebrates; examples are limited to a few species of decapod crustaceans and cephalopods. Is the marine environment less conducive to the establishment of dominance hierarchy structures, or does this just underline the lack of detailed behavioral information about most marine invertebrates? In this review, we highlight the published information about marine invertebrate dominance hierarchies, which involve ranks established through fights or displays. We focus on the method of hierarchy formation, examine the ecological implications of this population structure, and compare the habitat and behavioral characteristics of species that exhibit this behavior. Because dominance hierarchies can influence habitat use, population distributions, energetics, mating, resource exploitation, and population genetic structure, it is crucial to understand how this trait evolves and which species are likely to exhibit it. A better understanding of marine invertebrate hierarchies could change the way we think about population dynamics of some species and could have important implications for fisheries, conservation, or even modeling of social and economic inequality.

Effect of PREDICT on chemotherapy/trastuzumab recommendations in HER2-positive patients with early-stage breast cancer.

PREDICT is an online prognostication tool for early-stage breast cancer, which incorporates human epidermal growth factor 2 (HER2) status and stratifies absolute treatment benefits for hormone therapy, chemotherapy and trastuzumab. The present study compared historical multidisciplinary team (MDT) decisions regarding adjuvant treatment with PREDICT estimates, to determine whether certain patients are being over- or undertreated, particularly when stratified by age and oestrogen-receptor (ER) status. HER2-positive early-stage breast cancer cases over a five-year period at the Cambridge Breast Unit (Addenbrooke's Hospital, Cambridge, UK) were retrospectively reviewed. Patients receiving neo-adjuvant therapy were excluded. Adjuvant chemotherapy/trastuzumab recommendations based on PREDICT (<3%, no benefit; 3-5%, discuss treatment; and >5%, recommend treatment) were compared with actual MDT decisions. In total, 109 eligible patients were identified. The average age at diagnosis was 59.6 years, with 21 patients older than 70 years (19%). Four patients were predicted to gain an absolute benefit of >5% from chemotherapy/ trastuzumab, but were not offered treatment (all >70 years). Amongst the 19 patients aged >70 years predicted to benefit >3%, six were not offered treatment (32%). In the patients aged <69 years, there was evidence of overtreatment with adjuvant chemotherapy/trastuzumab in 8 out of 12 cases with <3% benefit using PREDICT. For all 20 patients with ER-negative tumours, the MDT and PREDICT decisions correlated, whilst for ER-positive cases, more than half (8 out of 14) were offered treatment despite a <3% predicted benefit. PREDICT can aid decision-making in HER2-positive early-stage breast cancer by identifying older patients at risk of undertreatment with chemotherapy/trastuzumab, and by reducing the overtreatment of patients with little predicted benefit, particularly in ER-positive disease.